Modeling and analysis of stoichiometric two-patch consumer-resource systems.
Ecological stoichiometry studies the balance of energy and multiple chemical elements in ecological interactions to establish how the laws of thermodynamics affect food-web dynamics and nutrient cycling in ecosystems. In this paper, we incorporate stoichiometric principles in a model with habitat heterogeneity and dispersal in order to better understand population growth dynamics. This model describes a situation where a resource is separated into two patches by a barrier. Growth of the resource in each patch is limited by soil fertility and self-crowding. The consumer disperses between the two patches and is not affected by the barrier. The consumer's growth is potentially limited by the phosphorus content of the acquired resource. Mathematical analysis of this model and simulations are performed. Several biological implications, including an observed "stoichiometric extinction effect," are demonstrated with simulation where the stoichiometric mechanism appears to promote extinction in a patchy environment. This is in sharp contrast to the notion that stoichiometry mechanism promotes diversity in spatially homogeneous settings. Another important result is the rediscovery of a simple and plausible biological mechanism that generates local and global extinction. In this setting, which can be considered a spatially mediated form of apparent competition, the dispersal of the consumer from the rich patch can des the growth of the resource in the poor patch and in some situations can lead to the extinction of the resource in the poor patch.


Function of steroidogenic factor 1 during development and differentiation of the reproductive system.
Intact reproductive development depends on steroids and other endocrine signals. Although recent discoveries have elucidated important steps of sexual differentiation, the intricate mechanisms that regulate the development of steroid-producing tissues remain elusive. In adults, complex feedback mechanisms determine the hypothalamic and pituitary regulation of steroid hormone biosynthesis. Steroidogenic factor 1 (SF-1), an orphan member of the nuclear receptor superfamily of proteins, plays a critical role in development and differentiation of the endocrine and reproductive systems. This review provides an overview of the function of SF-1, its mechanism of action, and a perspective on the interaction of SF-1 with other determinants of sexual differentiation. Whereas SF-1 is essential for the expression of numerous steroidogenic enzymes, its presence may not correlate with steroidogenic function. Moreover, diverse co-regulators modulate the influence of SF-1 on gene transcription. The significance of these interactions is discussed in the context of reproductive development and function. Other orphan or ligand-dependent nuclear proteins may share similar mechanisms.


Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target.
Atherosclerosis is a leading cause of cardiovascular diseases (CVD) worldwide and intimately linked to aging. This pathology is characterized by chronic inflammation, oxidative stress, gradual accumulation of low-density lipoproteins (LDL) particles and fibrous elements in focal areas of large and medium arteries. These fibrofatty lesions in the artery wall become progressively unstable and thrombogenic leading to heart attack, stroke or other severe heart ischemic syndromes. Elevated blood levels of LDL are major triggering events for atherosclerosis. A cascade of molecular and cellular events results in the atherosclerotic plaque formation, evolution, and rupture. Moreover, the senescence of multiple cell types present in the vasculature were reported to contribute to atherosclerotic plaque progression and destabilization. Classical therapeutic interventions consist of lipid-lowering drugs, anti-inflammatory and life style dispositions. Moreover, targeting oxidative stress by developing innovative antioxidant agents or boosting antioxidant systems is also a well-established strategy. Accumulation of senescent cells (SC) is also another important feature of atherosclerosis and was detected in various models. Hence, targeting SCs appears as an emerging therapeutic option, since senolytic agents favorably disturb atherosclerotic plaques. In this review, we propose a survey of the impact of inflammation, oxidative stress, and senescence in atherosclerosis; and the emerging therapeutic options, including thioredoxin-based approaches such as anti-oxidant, anti-inflammatory, and anti-atherogenic strategy with promising potential of senomodulation.


Caprin-1 influences autophagy-induced tumor growth and immune modulation in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.


Diffusion-weighted imaging abnormalities after percutaneous transluminal angioplasty and stenting for intracranial atherosclerotic disease.
The literature contains relatively few reports of distal embolism associated with intervention for intracranial atherosclerotic disease. Our purpose was to evaluate the frequency of thromboembolic events after percutaneous transluminal angioplasty (PTA) or stent placement in this setting by using diffusion-weighted (DW) imaging. Between October 1999 and January 2004, 16 consecutive patients with symptomatic intracranial arterial stenosis greater than 60% were treated with PTA or stent placement without a protection system. Whole-brain DW imaging was performed before and after intervention. DW imaging findings were retrospectively analyzed and divided into three groups according to new hyperintensities: type A was none; type B, a single lesion; and type C, multiple lesions. Nine type A, five type B, and three type C lesions were detected after the interventions. All hyperintense lesions were less than 5 mm in diameter. All type C lesions occurred in the context of internal carotid artery stenosis treated with stent placement. DW imaging abnormalities occurred most frequently when PTA followed by stent placement was performed for long internal carotid artery stenoses. No new neurologic deficits occurred in any patient. In this series, PTA or stent placement or both for intracranial atherosclerotic lesions was safe. New DW imaging abnormalities were less frequent in patients who underwent PTA alone or primary stent placement than in those receiving PTA followed by stent placement.


Comparison of RP-HPLC modes to analyse the N-glycome of the free-living nematode Pristionchus pacificus.
Pristionchus pacificus is a free-living nematode increasingly used as an organism for comparison to the more familiar model Caenorhabditis elegans. In this study, we examined the N-glycans of this organism isolated after serial release with peptide:N-glycosidases F and A; after fluorescent labelling with 2-aminopyridine, chromatographic fractionation by three types of RP-HPLC (with either classical C18, fused core C18 or alkylamide-bonded phases) followed by mass spectrometric analyses revealed key features of its N-glycome. In addition to paucimannosidic and oligomannosidic glycans typical of invertebrates, N-glycans with two core fucose residues were detected. Furthermore, a range of glycans carrying up to three phosphorylcholine residues was observed whereas, unlike C. elegans, no tetrafucosylated N-glycans were detected. Structures with three fucose residues, unusual methylation of core α1,3-fucose or with galactosylated fucose motifs were found in low amounts; these features may correlate with a different ensemble or expression of glycosyltransferase genes as compared to C. elegans. From an analytical perspective, both the alkylamide RP-amide and fused core C18 columns, as compared to a classical C18 material, offer advantages in terms of resolution and of elution properties, as some minor pyridylamino-labelled glycans (e.g. those carrying phosphorylcholine) appear in earlier fractions and so potential losses of such structures due to insufficient gradient length can be avoided.


Disposition of [14C]aztreonam in rats, dogs, and monkeys.
[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.


NOD receptor and TLR9 modulation in severe acute pancreatitis‑induced intestinal injury.
Severe acute pancreatitis (SAP) has a rapid onset and may cause multiple organ dysfunction syndrome (MODS), which has high mortality. Nucleotide binding oligomerization domain (NOD) receptor and Toll‑like receptor 9 (TLR9), a pattern recognition receptor in innate immunity, are involved in inflammation, immunity and pathogen recognition. The role and mechanism of the NOD receptor and TLR9 in early MODS of SAP‑induced intestinal injury, however, remain unclear. Wistar rats were divided into control, SAP, TLR9 inhibitor and NOD receptor activation groups. Reverse transcription‑quantitative polymerase chain reaction was used to analyze the expression of TLR9, NOD1 and NOD2 in the experimental treatment groups. Serum amylase, creatinine and alanine aminotransferase indices were measured, ELISA was used to determine the expression of tumor necrosis factor‑α (TNF‑α) and interleukin‑1β (IL‑1β) and western blot analysis was used to assess nuclear factor (NF)‑κB expression levels in intestinal tissues. Reactive oxygen species (ROS) levels and superoxide dismutase (SOD) activity were quantified by spectrometry. SAP and NOD receptor activation groups exhibited significantly elevated TLR9, NOD1, NOD2, TNF‑α, IL‑1β and nuclear factor (NF)‑κB levels compared with the control group. Furthermore, ROS production was increased, SOD activity was decreased and higher serum indices were exhibited, compared with the control group. The NOD receptor group presented more significant differences compared with the SAP group. The TLR9 inhibitor group exhibited opposite effects, with markedly decreased TLR9, NOD1, NOD2, TNF‑α, IL‑1β and NF‑κB levels. The TLR9 inhibitor group also presented reduced ROS production, increased SOD activity and lower serum indexes compared to the SAP group. The present study therefore indicated that NOD receptor and TLR9 may modulate the inflammatory response and further impact upon intestinal injury of SAP, via the regulation of NF‑κB expression and the oxidation/antioxidation balance, suggesting therapeutically targeting NOD receptor and TLR9 might be a useful approach for the treatment of severe acute pancreatitis.


Comparison of short and long courses of ampicillin for vaginal hysterectomy.
Administering perioperative antibiotic to reduce the morbidity associated with vaginal hysterectomy has become well accepted. Although both short and long courses of antibiotics are effective, the optimal length of treatment has not been well established by clinical studies. Our prospective study compared two groups of patients, one receiving a short course and the other a long course of ampicillin. Patients having vaginal hysterectomy were randomly assigned to the short or long course. Febrile morbidity, as well as serious morbidity and hospital stays, in the two groups was compared. Of 212 patients receiving the short course, 21 had febrile morbidity, while 14 of 215 patients receiving the long course had febrile morbidity. These rates were not significantly different. Furthermore, serious morbidity and length of hospital stay were not significantly different.


Intestinal anti-inflammatory activity of red wine extract: unveiling the mechanisms in colonic epithelial cells.
The development of new therapeutic approaches, combining efficacy and safety against intestinal inflammation, notably inflammatory bowel disease (IBD), has emerged as an important goal due to the significant side effects and the lack of effectiveness of standard current therapies. Recently, several studies described the health-promoting effects of red wine, including anti-inflammatory properties, but the molecular mechanisms underlying its beneficial role remain largely unknown. Red wine is rich in phenolic compounds and it has been suggested that the positive effect of red wine intake might be attributed not only to the antioxidant properties of these compounds but also to the modulation of signalling cascades in connection with physiological and pathophysiological conditions such as inflammatory processes. This study assesses the potential anti-inflammatory action of a red wine extract (RWE) enriched in polyphenols in a cellular model of intestinal inflammation using cytokines-stimulated HT-29 colon epithelial cells. RWE suppressed cytokines-induced IκB degradation and interleukin-8 production in a dose-dependent manner. Coherently, key inflammatory mediators downstream NF-κB activation; notably cyclooxygenase-2 and inducible nitric oxide synthase were maintained at low levels by RWE in the presence of the cytokines. Additionally, RWE inhibited both the increase of nitric oxide derived from iNOS and of protein tyrosine nitration, a biomarker of nitrosative stress that typically requires the reaction of nitric oxide with the superoxide radical. Taken together, the anti-inflammatory action of RWE, mechanistically supported by the modulation of cascades orchestrated by NF-κB and involving nitric oxide, suggests that RWE (a readily straightforward preparation when compared with the purification of specific compounds) may represent a simple and inexpensive therapeutic strategy in the context of intestinal inflammation.


Antipolysaccharide group-specific antibodies of Streptococcus pyogenes in children.
Evaluation of a new microtest for the detection of Streptococcus pyogenes group A antipolysaccharide antibodies in 996 control children and 562 streptococcal infections from 0 to 12 years. The case-list was divided in 4 groups, years 0-2. 2-4. 4-8. 8-12 for the evaluation of the age-related normality range. Under 2 years normal values between 60 and 120 U, from 2 to 12 years normal values under 240 U. In streptococcal infections identical patterns for the pathological values in the 4 age-ranges considered, with positivity percentage from 85% to 95%, thus confirming the same antibody response also in breast-fed children, unlike what occurs for ASO under 2 years, when the response is present only in 25% of the cases and in the 2-4 years age-range in 33.3%. Evident diagnostic superiority of MSK as compared with ASO in adenitis, pyodermic infections, bronchopneumopathies, acute tonsillitis at the onset of symptomatology. In rheumatic disease the percentage of positivity for MSK and ASO is similar, in post-streptococcal glomerulonephritis and in Schoenlein-Henoch syndrome the percentage of positivity for MSK is higher than for ASO. It is suggested the utility of insertion of MSK test in the routine assay for streptococcal infections diagnosis above all in children under 4 years and in infections with low or slow antigenic charge for 0-streptolysin.


Generation of bioactive peptides during food processing.
Large amounts of peptides are naturally generated in foods through the proteolysis phenomena taking place during processing. Such proteolysis is carried out either by endogenous enzymes in ripened foods or by the combined action of endogenous and microbial enzymes when fermented. Food proteins can also be isolated and hydrolysed by peptidases to produce hydrolysates. endo-peptidases act first followed by the successive action of exo-peptidases (mainly, tri- and di-peptidylpeptidases, aminopeptidases and carboxypeptidases). The generated peptides may be further hydrolysed through the gastrointestinal digestion resulting in a pool of peptides with different sequences and lengths, some of them with relevant bioactivity. However, these peptides should be absorbed intact through the intestinal barrier and reach the blood stream to exert their physiological action. This manuscript is reporting the enzymatic routes and strategies followed for the generation of bioactive peptides.


Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome.
Corticobasal ganglia neuronal ensembles bring automatic motor skills into voluntary control and integrate them into ongoing motor behavior. A 5% decrease in caudate (Cd) nucleus volume is the most consistent structural finding in the brain of patients with Tourette syndrome (TS), but the cellular abnormalities that underlie this decrease in volume are unclear. In this study the density of different types of interneurons and medium spiny neurons (MSNs) in the striatum was assessed in the postmortem brains of 5 TS subjects as compared with normal controls (NC) by unbiased stereological analyses. TS patients demonstrated a 50%-60% decrease of both parvalbumin (PV)+ and choline acetyltransferase (ChAT)+ cholinergic interneurons in the Cd and the putamen (Pt). Cholinergic interneurons were decreased in TS patients in the associative and sensorimotor regions but not in the limbic regions of the striatum, such that the normal gradient in density of cholinergic cells (highest in associative regions, intermediate in sensorimotor and lowest in limbic regions) was abolished. No significant difference was present in the densities of medium-sized calretinin (CR)+ interneurons, MSNs, and total neurons. The selective deficit of PV+ and cholinergic striatal interneurons in TS subjects may result in an impaired cortico/thalamic control of striatal neuron firing in TS.


Unraveling the origin of Cladocera by identifying heterochrony in the developmental sequences of Branchiopoda.
One of the most interesting riddles within crustaceans is the origin of Cladocera (water fleas). Cladocerans are morphologically diverse and in terms of size and body segmentation differ considerably from other branchiopod taxa (Anostraca, Notostraca, Laevicaudata, Spinicaudata and Cyclestherida). In 1876, the famous zoologist Carl Claus proposed with regard to their origin that cladocerans might have evolved from a precociously maturing larva of a clam shrimp-like ancestor which was able to reproduce at this early stage of development. In order to shed light on this shift in organogenesis and to identify (potential) changes in the chronology of development (heterochrony), we investigated the external and internal development of the ctenopod Penilia avirostris and compared it to development in representatives of Anostraca, Notostraca, Laevicaudata, Spinicaudata and Cyclestherida. The development of the nervous system was investigated using immunohistochemical labeling and confocal microscopy. External morphological development was followed using a scanning electron microscope and confocal microscopy to detect the autofluorescence of the external cuticle. In Anostraca, Notostraca, Laevicaudata and Spinicaudata development is indirect and a free-swimming nauplius hatches from resting eggs. In contrast, development in Cyclestherida and Cladocera, in which non-swimming embryo-like larvae hatch from subitaneous eggs (without a resting phase) is defined herein as pseudo-direct and differs considerably from that of the other groups. Both external and internal development in Anostraca, Notostraca, Laevicaudata and Spinicaudata is directed from anterior to posterior, whereas in Cyclestherida and Cladocera differentiation is more synchronous. In this study, developmental sequences from representatives of all branchiopod taxa are compared and analyzed using a Parsimov event-pairing approach. The analysis reveals clear evolutionary transformations towards Cladocera and the node of Cladoceromorpha which correspond to distinct heterochronous signals and indicate that the evolution of Cladocera was a stepwise process. A switch from a strategy of indirect development to one of pseudo-direct development was followed by a shift in a number of morphological events to an earlier point in ontogenesis and simultaneously by a reduction in the number of pre-metamorphosis molts. A compression of the larval phase as well as a shortening of the juvenile phase finally leads to a precocious maturation and is considered as a gradual progenetic process.


Contraction-Induced Loss of Plasmalemmal Electrophysiological Function Is Dependent on the Dystrophin Glycoprotein Complex.
Weakness and atrophy are key features of Duchenne muscular dystrophy (DMD). Dystrophin is one of the many proteins within the dystrophin glycoprotein complex (DGC) that maintains plasmalemmal integrity and cellular homeostasis. The dystrophin-deficient mdx mouse is also predisposed to weakness, particularly when subjected to eccentric (ECC) contractions due to electrophysiological dysfunction of the plasmalemma. Here, we determined if maintenance of plasmalemmal excitability during and after a bout of ECC contractions is dependent on intact and functional DGCs rather than, solely, dystrophin expression. Wild-type (WT) and dystrophic mice (mdx, mL172H and Sgcb-/- mimicking Duchenne, Becker and Limb-girdle Type 2E muscular dystrophies, respectively) with varying levels of dystrophin and DGC functionality performed 50 maximal ECC contractions with simultaneous torque and electromyographic measurements (M-wave root-mean-square, M-wave RMS). ECC contractions caused all mouse lines to lose torque (p<0.001); however, deficits were greater in dystrophic mouse lines compared to WT mice (p<0.001). Loss of ECC torque did not correspond to a reduction in M-wave RMS in WT mice (p=0.080), while deficits in M-wave RMS exceeded 50% in all dystrophic mouse lines (p≤0.007). Moreover, reductions in ECC torque and M-wave RMS were greater in mdx mice compared to mL172H mice (p≤0.042). No differences were observed between mdx and Sgcb-/- mice (p≥0.337). Regression analysis revealed ≥98% of the variance in ECC torque loss could be explained by the variance in M-wave RMS in dystrophic mouse lines (p<0.001) but not within WT mice (R 2=0.211; p=0.155). By comparing mouse lines that had varying amounts and functionality of dystrophin and other DGC proteins, we observed that (1) when all DGCs are intact, plasmalemmal action potential generation and conduction is maintained, (2) deficiency of the DGC protein β-sarcoglycan is as disruptive to plasmalemmal excitability as is dystrophin deficiency and, (3) some functionally intact DGCs are better than none. Our results highlight the significant role of the DGC plays in maintaining plasmalemmal excitability and that a collective synergism (via each DGC protein) is required for this complex to function properly during ECC contractions.


Intense near-infrared emission from ZnO-LiYbO(2) hybrid phosphors through efficient energy transfer from ZnO to Yb(3+).
The ZnO-LiYbO(2) hybrid phosphors were sintered by the solid-state reaction method, in which the intense near-infrared emission around 1000 nm due to Yb(3+ 2)F(5/2)-->(2)F(7/2) transition was obtained due to the efficient energy transfer from ZnO to Yb(3+) ions. The growth of the LiYbO(2) crystal and the formation of the diffusion layer between LiYbO(2) and ZnO were confirmed by XRD, SEM and EDX studies. The high efficient energy transfer is benefited from the inter-diffusion of Li(+), Yb(3+) and Zn(2+) in the diffusion region. The spectroscopy results clearly indicated that the ZnO-LiYbO(2) hybrid phosphors can harvest the energy from near-UV photons in a broad wavelength region and effectively convert them into Yb(3+) near-infrared emission.


Molecular basis of atrial fibrillation: a dream or a reality?
AF is a difficult disease to treat because of the numerous (ischemic, metabolic, inflammatory, structural) mechanisms contributing to its etiology. AF persistence requires both an adequate tissue substrate for reentrant activity and triggers to initiate the arrhythmia. In a few interesting instances, AF may have a monogenic cause. Although there are common electrophysiologic characteristics of myocytes from a variety of AF models and clinical presentations, it is unrealistic to expect that all patients will respond equally to the same interventions. Thus, patients with AF of an inflammatory etiology may respond better to anti-inflammatory therapies, whereas those with enlarged atria secondary to valvular disease may require surgery. Some may respond better to ablation than others. However, the heterogeneity of the substrate does not negate the value of searching for the underlying molecular mechanisms. As we begin to comprehend these mechanisms in greater detail, the dream of using individualized rational therapies will come closer to reality.


Barriers and attitudes influencing non-engagement in a peer feedback model to inform evidence for GP appraisal.
The UK general practitioner (GP) appraisal system is deemed to be an inadequate source of performance evidence to inform a future medical revalidation process. A long-running voluntary model of external peer review in the west of Scotland provides feedback by trained peers on the standard of GP colleagues' core appraisal activities and may 'add value' in strengthening the robustness of the current system in support of revalidation. A significant minority of GPs has participated in the peer feedback model, but a clear majority has yet to engage with it. We aimed to explore the views of non-participants to identify barriers to engagement and attitudes to external peer review as a means to inform the current appraisal system. We conducted semi-structured interviews with a sample of west of Scotland GPs who had yet to participate in the peer review model. A thematic analysis of the interview transcriptions was conducted using a constant comparative approach. 13 GPs were interviewed of whom nine were males. Four core themes were identified in relation to the perceived and experienced 'value' placed on the topics discussed and their relevance to routine clinical practice and professional appraisal: 1. Value of the appraisal improvement activity. 2. Value of external peer review. 3. Value of the external peer review model and host organisation and 4. Attitudes to external peer review. GPs in this study questioned the 'value' of participation in the external peer review model and the national appraisal system over the standard of internal feedback received from immediate work colleagues. There was a limited understanding of the concept, context and purpose of external peer review and some distrust of the host educational provider. Future engagement with the model by these GPs is likely to be influenced by policy to improve the standard of appraisal and contractual related activities, rather than a self-directed recognition of learning needs.


Uncovering the Hidden World of Aqueous Humor Proteins for Discovery of Biomarkers for Marfan Syndrome.
Ectopia lentis is a hallmark of Marfan syndrome (MFS), a genetic connective tissue disorder affecting 1/5000 to 1/10 000 individuals worldwide. Early detection in ophthalmology clinics and timely intervention of cardiovascular complications can be lifesaving. In this study, a modified proteomics workflow with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based data-independent acquisition (DIA) and field asymmetric ion mobility spectrometry (FAIMS) to profile the proteomes of aqueous humor (AH) and lens tissue from MFS children with ectopia lentis is utilized. Over 2300 and 2938 comparable proteins are identified in AH and the lens capsule, respectively. Functional enrichment analyses uncovered dysregulation of complement and coagulation-related pathways, collagen binding, and cell adhesion in MFS. Through weighted correlation network analysis (WGCNA) and machine learning, distinct modules associated with clinical traits are constructed and a unique biomarker panel (Q14376, Q99972, P02760, Q07507; gene names: GALE, MYOC, AMBP, DPT) is defined. These biomarkers are further validated using advanced parallel reaction monitoring (PRM) in an independent patient cohort. The results provide novel insights into the proteome characterization of ectopia lentis and offer a promising approach for developing a valuable biomarker panel to aid in the early diagnosis of Marfan syndrome via AH proteome.


Dynamic modulation of the action observation network by movement familiarity.
When watching another person's actions, a network of sensorimotor brain regions, collectively termed the action observation network (AON), is engaged. Previous research suggests that the AON is more responsive when watching familiar compared with unfamiliar actions. However, most research into AON function is premised on comparisons of AON engagement during different types of task using univariate, magnitude-based approaches. To better understand the relationship between action familiarity and AON engagement, here we examine how observed movement familiarity modulates AON activity in humans using dynamic causal modeling, a type of effective connectivity analysis. Twenty-one subjects underwent fMRI scanning while viewing whole-body dance movements that varied in terms of their familiarity. Participants' task was to either predict the next posture the dancer's body would assume or to respond to a non-action-related attentional control question. To assess individuals' familiarity with each movement, participants rated each video on a measure of visual familiarity after being scanned. Parametric analyses showed more activity in left middle temporal gyrus, inferior parietal lobule, and inferior frontal gyrus as videos were rated as increasingly familiar. These clusters of activity formed the regions of interest for dynamic causal modeling analyses, which revealed attenuation of effective connectivity bidirectionally between parietal and temporal AON nodes when participants observed videos they rated as increasingly familiar. As such, the findings provide partial support for a predictive coding model of the AON, as well as illuminate how action familiarity manipulations can be used to explore simulation-based accounts of action understanding.


Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine.
This is the first prospectively randomized study of the use of melphalan/prednisone and colchicine in the treatment of primary systemic amyloidosis. One hundred one patients were stratified according to their dominant clinical manifestation. Forty-nine patients initially received melphalan/prednisone and eight subsequently had colchicine added to their regimen. Fifty-two patients initially received colchicine and 35 subsequently required melphalan/prednisone because of progressive disease. There was no difference in survival when the two groups were analyzed in aggregate (melphalan/prednisone, 25.2 months versus colchicine, 18 months; p = 0.23). When the survival of patients receiving only one regimen was analyzed or when survival was analyzed from the time of entry into the study to the time of death or progression of disease, significant differences (p less than 0.001 and p less than 0.0001, respectively) were evident, favoring melphalan/prednisone. This study suggests that melphalan/prednisone is superior to colchicine in the treatment of primary amyloidosis, but to confirm this impression, a study without a crossover group is necessary.


Incidence and Trends of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Population-Based Study.
Few studies have investigated the incidence of PSP and CBS in the population. To examine the incidence of and trends in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in a population-based cohort of residents of Olmsted County, MN. We used the 1991-2005 population-based, Olmsted County Parkinsonism-cohort study, defined via the Rochester Epidemiology Project. A movement-disorder specialist reviewed medical records, to confirm PSP and CBS diagnoses. We identified 21 patients with these diagnoses 1991-2005 : 18 (85.7%), PSP; 3 (14.3%), CBS. The median diagnosis age was 78 (range: 66-88). 13/21 (62.0%) were male. MRI was performed pre-diagnosis in 11 patients (8 PSP and 3 CBD); 10 showed atrophy consistent with clinical diagnoses. We observed concordance between clinical and pathological diagnoses in two PSP patients who underwent autopsy. Combined incidence for PSP and CBS in Olmsted County was 3.1 per 100,000 person-years (2.6 per 100,000 person-years, PSP; 0.4 per 100,000 person-years, CBS). Incidence was higher in men (4.5, 95% CI, 2.0-7.0) than women (1.8, 95% CI, 0.5-2.9). A combined, significant trend of increasing incidence was observed between 1991 and 2005 (B=0.69, 95% CI 0.42, 0.96, p<0.001). Median time from symptom onset to death among both groups was 6 years (range PSP, 1-10 years; range CBS, 3-8 years). The combined incidence for PSP and CBS was 3.1 per 100,000 person-years, higher in men than women. We observed a significant increase in both PSP and CBS, likely due to advancing imaging technology and improved diagnostic ability among physicians.


The Seattle-King County healthy homes project: implementation of a comprehensive approach to improving indoor environmental quality for low-income children with asthma.
Pediatric asthma is a growing public health issue, disproportionately affecting low-income people and people of color. Exposure to indoor asthma triggers plays an important role in the development and exacerbation of asthma. We describe the implementation of the Seattle-King County Healthy Homes Project, a randomized, controlled trial of an outreach/education intervention to improve asthma-related health status by reducing exposure to allergens and irritants in the home. We randomly assigned 274 low-income children with asthma ages 4-12 to either a high- or a low-intensity group. In the high-intensity group, community health workers called Community Home Environmental Specialists (CHES) conducted initial home environmental assessments, provided individualized action plans, and made additional visits over a 12-month period to provide education and social support, encouragement of participant actions, provision of materials to reduce exposures (including bedding encasements), assistance with roach and rodent eradication, and advocacy for improved housing conditions. Members of the low-intensity group received the initial assessment, home action plan, limited education during the assessment visit, and bedding encasements. We describe the recruitment and training of CHES and challenges they faced and explain the assessment and exposure reduction protocols addressing dust mites, mold, tobacco smoke, pets, cockroaches, rodents, dust, moisture, and toxic or hazardous chemicals. We also discuss the gap between the practices recommended in the literature and what is feasible in the home. We accomplished home interventions and participants found the project very useful. The project was limited in resolving structural housing quality issues that contributed to exposure to indoor triggers.


General cognitive decline does not account for older adults' worse emotion recognition and theory of mind.
Older adults have both worse general cognition and worse social cognition. A frequent suggestion is that worse social cognition is due to worse general cognition. However, previous studies have often provided contradictory evidence. The current study examined this issue with a more extensive battery of tasks for both forms of cognition. We gave 47 young and 40 older adults three tasks to assess general cognition (processing speed, working memory, fluid intelligence) and three tasks to assess their social cognition (emotion and theory-of-mind). Older adults did worse on all tasks and there were correlations between general and social cognition. Although working memory and fluid intelligence were unique predictors of performance on the Emotion Photos task and the Eyes task, Age Group was a unique predictor on all three social cognition tasks. Thus, there were relations between the two forms of cognition but older adults continued to do worse than young adults even after accounting for general cognition. We argue that this pattern of results is due to some overlap in brain areas mediating general and social cognition, but also independence, and with a differential rate of decline in brain areas dedicated to general cognition versus social cognition.


Ethics for Laboratory Medicine.
Laboratory medicine, like other areas of medicine, is obliged to adhere to high ethical standards. There are particular ethical issues that are unique to laboratory medicine and other areas in which ethical issues uniquely impact laboratory practice. Despite this, there is variability in ethics education within the profession. This review provides a foundation for the study of ethics within laboratory medicine. The Belmont Report identifies 3 core principles in biomedical ethics: respect for persons (including autonomy), beneficence (and its corollary nonmalfeasance), and justice. These core principles must be adhered to in laboratory medicine. Informed consent is vital to maintain patient autonomy. However, balancing patient autonomy with the desire for beneficence can sometimes be difficult when patients refuse testing or treatment. The use of leftover or banked samples is fundamental to the ability to do research, create reference intervals, and develop new tests, but it creates problems with consent. Advances in genetic testing have created unique ethical issues regarding privacy, incidental findings, and informed consent. As in other professions, the emergence of highly contagious and deadly infectious diseases poses a difficult ethical dilemma of helping patients while protecting healthcare workers. Although many clinical laboratorians do not see or treat patients, they must be held accountable to the highest ethical and professional behavior. Recognition and understanding of ethical issues are essential to ethical practice of laboratory medicine.


Deep learning facilitates fully automated brain image registration of optoacoustic tomography and magnetic resonance imaging.
Multispectral optoacoustic tomography (MSOT) is an emerging optical imaging method providing multiplex molecular and functional information from the rodent brain. It can be greatly augmented by magnetic resonance imaging (MRI) which offers excellent soft-tissue contrast and high-resolution brain anatomy. Nevertheless, registration of MSOT-MRI images remains challenging, chiefly due to the entirely different image contrast rendered by these two modalities. Previously reported registration algorithms mostly relied on manual user-dependent brain segmentation, which compromised data interpretation and quantification. Here we propose a fully automated registration method for MSOT-MRI multimodal imaging empowered by deep learning. The automated workflow includes neural network-based image segmentation to generate suitable masks, which are subsequently registered using an additional neural network. The performance of the algorithm is showcased with datasets acquired by cross-sectional MSOT and high-field MRI preclinical scanners. The automated registration method is further validated with manual and half-automated registration, demonstrating its robustness and accuracy.


Dendritic cells regulate high-speed interstitial T cell migration in the lymph node via LFA-1/ICAM-1.
T lymphocytes vigorously migrate within the paracortex of lymph nodes (LNs) in search of cognate Ags that are presented by dendritic cells (DCs). However, the mechanisms that support T cells to exert the highest motility in a densely packed LN microenvironment are not fully understood. Two-photon microscopy using LN tissue slices revealed that LFA-1 and ICAM-1 were required for high-velocity migration (>10 μm/min) with relatively straight movement. Importantly, ICAM-1 expressed by myeloid lineages, most likely DCs, but not stromal cells or lymphocytes, was sufficient to support the high-velocity migration. Visualizing DCs in the LN from CD11c-EYFP mice showed that T cells traveled over thin dendrites and the body of DCs. Interestingly, DCs supported T cell motility in vitro in chemokine- and ICAM-1-dependent manners. Moreover, an acute lymphopenic environment in the LN significantly increased LFA-1 dependency for T cell migration, indicating that lymphocyte density modulates the use of LFA-1. Therefore, our results indicate that LFA-1/ICAM-1-dependent interactions between T cells and DCs play a crucial role not only in supporting firm arrest during Ag recognition but also in facilitating the Ag scanning processes.


Associative memory cells: Formation, function and perspective.
Associative learning and memory are common activities in life, and their cellular infrastructures constitute the basis of cognitive processes. Although neuronal plasticity emerges after memory formation, basic units and their working principles for the storage and retrieval of associated signals remain to be revealed. Current reports indicate that associative memory cells, through their mutual synapse innervations among the co-activated sensory cortices, are recruited to fulfill the integration, storage and retrieval of multiple associated signals, and serve associative thinking and logical reasoning. In this review, we aim to summarize associative memory cells in their formation, features and functional impacts.


RMS tactile scale: An innovative tactile anxiety scale for visually impaired children.
Behavior guidance is considered to be the backbone of pediatric dentistry which differentiates us from the other fields in dental sciences. Anxiety and fear being the primary concern in pediatric patients, has to be taken into consideration for the visually impaired children too. In the present study, an innovative anxiety scale RMS tactile scale (RMS-TS) was designed for the visually impaired children. Introducing newer concept other than Braille in the dental clinic for such patients can help in coping up and bringing out positive behavior in the special children. The study aimed to validate and assess the efficacy of RMS-TS for visually impaired child and compare it with modified dental anxiety scale (MDAS) and Braille scale. A total of hundred children of age 12-15 years from the special school were selected for the study. MDAS, RMS-TS, and Braille scale were used to determine the pretreatment anxiety scores in the visually impaired children. The validity of the RMS-TS in the pretreatment anxiety in the assessment of child's dental anxiety is supported by its strong correlation with both the scales. The RMS-TS can be reliable anxiety assessment scale for measuring child's dental anxiety in visually impaired children. It can be used alone or in combination with other methods to improve assessment of dental anxiety.


COSMIC INHERITANCE RULES: IMPLICATIONS FOR HEALTH CARE AND SCIENCE.
Countering the trend in specialization, we advocate the trans-disciplinary monitoring of blood pressure and heart rate for signatures of environmental cyclic and other variabilities in space as well as terrestrial weather on the one hand, and for surveillance of personal and societal health on the other hand. New rules (if confirmed novel laws) emerge as we recognize our inheritance from the cosmos of cycles that constitute and characterize life and align them with inheritance from parents. In so doing, we happen to follow the endeavors of Gregor Mendel, who recognized the segregation and independent assortment of what became known as genes. Circadians, rhythms with periods, τ, between 20 and 28 hours, and cycles with frequencies that are higher (ultradian) or lower (infradian) than circadian, are genetically anchored. An accumulating long list of very important but aeolian (nonstationary) infradian cycles, characterizing the incidence patterns of sudden cardiac death, suicide and terrorism, with drastically different τs, constitutes the nonphotic (corpuscular emission from the sun, heliogeomagnetics, ultraviolet flux, gravitation) Cornélissen-series.


Applying low coverage whole genome sequencing to detect malignant ovarian mass.
To evaluate whether low coverage whole genome sequencing is suitable for the detection of malignant pelvic mass and compare its diagnostic value with traditional tumor markers. We enrolled 63 patients with a pelvic mass suspicious for ovarian malignancy. Each patient underwent low coverage whole genome sequencing (LCWGS) and traditional tumor markers test. The pelvic masses were finally confirmed via pathological examination. The copy number variants (CNVs) of whole genome were detected and the Stouffers Z-scores for each CNV was extracted. The risk of malignancy (RM) of each suspicious sample was calculated based on the CNV counts and Z-scores, which was subsequently compared with ovarian cancer markers CA125 and HE4, and the risk of ovarian malignancy algorithm (ROMA). Receiver Operating Characteristic Curve (ROC) were used to access the diagnostic value of variables. As confirmed by pathological diagnosis, 44 (70%) patients with malignancy and 19 patients with benign mass were identified. Our results showed that CA125 and HE4, the CNV, the mean of Z-scores (Zmean), the max of Z-scores (Zmax), the RM and the ROMA were significantly different between patients with malignant and benign masses. The area under curve (AUC) of CA125, HE4, CNV, Zmax, and Zmean was 0.775, 0.866, 0.786, 0.685 and 0.725 respectively. ROMA and RM showed similar AUC (0.876 and 0.837), but differed in sensitivity and specificity. In the validation cohort, the AUC of RM was higher than traditional serum markers. In conclusion, we develop a LCWGS based method for the identification of pelvic mass of suspicious ovarian cancer. LCWGS shows accurate result and could be complementary with the existing diagnostic methods.


Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients.
The aim of this study was to evaluate the efficacy of pegfilgrastim, in combination with salvage chemotherapy, in mobilizing CD34(+) stem cells into the peripheral blood of pretreated lymphoma patients. This was an open-label phase II study including 25 pretreated patients (Hodgkin's disease=4; aggressive non-Hodgkin's lymphoma=21). The primary end-point of the study was the successful mobilization of a target cell dose of 2x10(6) CD34(+) cells/kg in lymphoma patients receiving ifosfamide, epirubicin and etoposide (IEV) chemotherapy and a fixed dose (6 mg) of pegfilgrastim given as single subcutaneous injection. Following chemotherapy, all patients had grade 4 neutropenia that lasted a median of 1.5 days (1-3). Pegfilgrastim treatment was well tolerated and only 2/25 patients required pain-control medication. CD34+ cells were mobilized in all patients. The median (range) peak value of peripheral blood CD34+ cells after IEV chemotherapy and pegfilgrastim was 141x10(6)/L (12.8-386) and occurred almost invariably on day +14 (13-16). Twenty-three of the 25 patients underwent a single standard volume leukapheresis to collect a median of 8.7x10(6) CD34(+) cells/kg (1.78-17.3). Twenty four/25 patients (96%) reached the target cell dose of 2x10(6) CD34(+) cells/kg. High concentrations of circulating CD34+ cells (> 50x10(6)/L) were observed for several days after the achievement of the peak value. All the study patients were transplanted with their pegfilgrastim-mobilized CD34(+) cells and showed a rapid and sustained engraftment after high-dose chemotherapy. Our results show that pegfilgrastim as an adjunct to chemotherapy is a predictable and highly effective mobilization regimen in pretreated lymphoma patients.


Robust Machine Learning Variable Importance Analyses of Medical Conditions for Health Care Spending.
To propose nonparametric double robust machine learning in variable importance analyses of medical conditions for health spending. 2011-2012 Truven MarketScan database. I evaluate how much more, on average, commercially insured enrollees with each of 26 of the most prevalent medical conditions cost per year after controlling for demographics and other medical conditions. This is accomplished within the nonparametric targeted learning framework, which incorporates ensemble machine learning. Previous literature studying the impact of medical conditions on health care spending has almost exclusively focused on parametric risk adjustment; thus, I compare my approach to parametric regression. My results demonstrate that multiple sclerosis, congestive heart failure, severe cancers, major depression and bipolar disorders, and chronic hepatitis are the most costly medical conditions on average per individual. These findings differed from those obtained using parametric regression. The literature may be underestimating the spending contributions of several medical conditions, which is a potentially critical oversight. If current methods are not capturing the true incremental effect of medical conditions, undesirable incentives related to care may remain. Further work is needed to directly study these issues in the context of federal formulas.


Time course of gene expression of inflammatory mediators in rat lung after diesel exhaust particle exposure.
Diesel exhaust particles (DEPs) at three concentrations (5, 35, and 50 mg/kg body weight) were instilled into rats intratracheally. We studied gene expression at 1, 7, and 30 days postexposure in cells obtained by bronchoalveolar lavage (BAL) and in lung tissue. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we measured the mRNA levels of eight genes [interleukin (IL)-1beta, IL-6, IL-10, iNOS (inducible nitric oxide synthase), MCP-1 (monocyte chemoattractant protein-1), MIP-2 (macrophage inflammatory protein-2), TGF-beta1 (transforming growth factor-beta1), and TNF-alpha (tumor necrosis factor-alpha )] in BAL cells and four genes [IL-6, ICAM-1 (intercellular adhesion molecule-1), GM-CSF (granulocyte/macrophage-colony stimulating factor), and RANTES (regulated upon activation normal T cell expressed and secreted)] in lung tissue. In BAL cells on day 1, high-dose exposure induced a significant up-regulation of IL-1beta, iNOS, MCP-1, and MIP-2 but no change in IL-6, IL-10, TGF-beta1, and TNF-alpha mRNA levels. There was no change in the mRNA levels of IL-6, RANTES, ICAM-1, and GM-CSF in lung tissue. Nitric oxide production and levels of MCP-1 and MIP-2 were increased in the 24-hr culture media of alveolar macrophages (AMs) obtained on day 1. IL-6, MCP-1, and MIP-2 levels were also elevated in the BAL fluid. BAL fluid also showed increases in albumin and lactate dehydrogenase. The cellular content in BAL fluid increased at all doses and at all time periods, mainly due to an increase in polymorphonuclear leukocytes. In vitro studies in AMs and cultured lung fibroblasts showed that lung fibroblasts are a significant source of IL-6 and MCP-1 in the lung.


Cloning and sequencing of a cDNA encoding alpha-glucosidase from sugar beet.
A cDNA encoding sugar beet alpha-glucosidase was cloned from a library constructed from mRNA of suspension-cultured cells. The cDNA, 3056 bp in length, had an open reading frame encoding a polypeptide of 913 amino acid residues with a molecular mass of 102,078 Da, included only one of four regions which were conserved in the alpha-amylase family of enzymes. The deduced amino acid sequence from the analysis of the cDNA contained the sequences of the proteolysis peptides and the active site region peptide of sugar beet alpha-glucosidase. The primary structure indicated relatively high homology in the range of 28.2 to 54.3% to those for other alpha-glucosidases. The highest homology was found in barley alpha-glucosidase.


A qualitative evaluation of a mentoring program for Aboriginal health workers and allied health professionals.
Effective partnerships between Aboriginal Health Workers and non-Aboriginal health professionals are essential to achieve Aboriginal health outcomes. This study aimed to evaluate a mentoring workforce development strategy for Aboriginal Health Workers and non-Aboriginal allied health professionals. Thirty-four Aboriginal Health Workers and non-Aboriginal health professionals were recruited to the mentoring program where they were paired and established a learning relationship for approximately six months. A qualitative evaluation with thirty of the participants was undertaken involving in-depth interviews at the completion of the program. A total of 18 mentoring partnerships were formed across Victoria. The data revealed three key themes in relation to the evaluation of the program: (1) The mentoring program facilitated two-way learning, (2) The Aboriginal Health Workers and non-Aboriginal health professional participants reported being able to meet their identified learning needs through the partnership, (3) The capacity to improve practice was facilitated through readiness to learn and change practice and personal attributes of the participants, as well as organisation and management support. Peer mentoring between Aboriginal and non-Aboriginal health workforce was found to be a powerful mechanism to promote two-way learning that has the capacity to meet learning needs and promote practice improvement. Peer mentoring may be part of a multi-strategy approach to the development of the Aboriginal health workforce.


Thyroid hemiagenesis is a rare variant of thyroid dysgenesis with a familial component but without Pax8 mutations in a cohort of 22 cases.
Thyroid hemiagenesis is a rare form of thyroid dysgenesis of which some familial cases have been reported, including one associated with a heterozygous mutation in the Pax8 gene. However, the physiopathology remains not well known. The objectives of this study were 1) to describe the clinical features, 2) to look for familial clustering, and 3) to search for Pax8 mutations in a relatively large cohort of affected patients. A family history of thyroid dysgenesis was found in nine patients (40%), whose affected relatives had ectopic thyroid (n = 4), athyreosis (n = 1), thyroid hemiagenesis (n = 2), or thyroglossal duct cysts (n = 2). Screening for Pax8 mutations identified abnormal migration profiles by SSCP analysis in 3 patients, but direct sequencing did not show coding region mutations in any of the 22 patients. In conclusion, this study provides the first evidence that thyroid hemiagenesis can occur as a familial disorder associated with any form of thyroid dysgenesis. This finding supports both a common underlying mechanism to the various abnormalities in thyroid development and a role for genetic factors; however, our results from Pax8 analysis suggest that this gene may not be a key factor.


[Single "early" action potential cause by Ni2+ ions in true pacemaker cells of the sinoatrial ring of the dace heart].
Single "early" action potentials (AP) or "early" postdepolarization (EAD) were recorded in multicellular stripes working in the regimen of true pacemaker cells located in the basis of the sinoatrial valve of the dace (Leuciscus rutilus) heart after Ni2+ (0.3 mM) were added to superfused solution on the 15 th min. The standard microelectrode technique was used. The appearance of single EAD was preceded by increase of AP spike duration almost 1.5-fold due to increase of the duration of a final repolarization phase and of diastolic depolarization. EADs appeared at different levels of repolarization from -20 to -60 mV. EAD's amplitude was lower than the AP proper. The effect is reversible. Nifedipine (2 microM) decreased by 20% the AP duration to 50% repolarization in the cells of atrial type. In case the stripes were primarily subjected to nifedipine effect and then even after a long procedure of washout, the Ni2+ (0.3 mM) did not cause EADs. The hypothesis has been tested of what is the main reason of single EAD appearance in pacemaker cells under the effect of Ni2+; it is either blocking Ca release from the cell by Ni2+, or reactivation of L-type Ca-channels' conductivity. The analysis of the data obtained leads to the conclusion that 30-50% Na-Ca-exchangers block is the basic reason of single EAD appearance in pacemaker cells.


Ghost optical coherence tomography.
We demonstrate experimentally ghost optical coherence tomography using a broadband incoherent supercontinuum light source with shot-to-shot random spectral fluctuations. The technique is based on ghost imaging in the spectral domain where the object is the spectral interference pattern generated from an optical coherence tomography interferometer in which a physical sample is placed. The axial profile of the sample is obtained from the Fourier transform of the correlation between the spectrally resolved intensity fluctuations of the supercontinuum and the integrated signal measured at the output of the interferometer. The results are in excellent agreement with measurements obtained from a conventional optical coherence tomography system.


[Adverse drug reactions in area I in Asturias].
The objective of this study was to know the incidence of adverse drug reactions in a group of children sent to our office by their pediatrician under the suspicion of having suffered a drug reaction. Ninety-eight children were retrospectively studied. Family background, clinical picture, drugs involved, time elapsing between the onset of symptoms and the date of the study, association to other allergic conditions and diagnostic methods used "in vivo" and "in vitro" were evaluated. Mean age of the patients was 4 years with 53.5% being female and 46.5% male. Positive drug allergy in the family background was found in 22%. The clinical picture showed urticaria and angioedema in 36%, morbiliform eruption in 31%, urticaria in 20%, only angioedema in 9% and other symptoms in 4%. Drugs involved included betalactams (78%), macrolides (17.5%) and others (less than 9%). The mean time elapsed between the onset of symptoms and the date of study was 2 years. There was association to other allergic conditions in 18% (50% in the cases in which the drug allergy was confirmed). RAST to penicillin G and V, amoxicillin and ampicillin was done in 28 cases (betalactams), being negative in all of them. Skin tests were carried out in 21 cases (betalactams), being positive in 19% (66% among the confirmed cases). In all but two cases a controlled provocation test was carried out, being positive only in 8. 1) The presence of adverse drug reactions is confirmed in only 9% of the cases. 2) Confirmation of the clinical history and the provocation test as the most reliable diagnostic methods currently available. 3) Acceptable sensitivity of the skin tests in the case of betalactams. 4) Null sensitivity of the RAST in the case of betalactams.


Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha.
The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappaB (NF-kappaB) via IkappaBalpha phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor alpha (TNFalpha)-induced IkappaBalpha degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-kappaB. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-kappaB via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating IkappaBalpha that is critical for the activation of NF-kappaB-directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors.


The effect of diet on the Vervet monkey endocrine pancreas.
Vervet monkeys (Cercopithecus aethiops) used for pancreatic endocrine cell distribution studies were found to have been maintained on different diets. Although the effect of dietary changes on the exocrine pancreas has been described in several animals, little, apart from the effect of malnutrition, has been reported for the endocrine pancreas. Reported here are pancreatic endocrine cell distributions in monkeys on a standard diet (n = 3) compared with monkeys on an atherogenic diet (n = 3). Quantitation of immunolabelled pancreatic endocrine cell types revealed a significant 80% increase in A (glucagon) cell volume in monkeys on an atherogenic diet concomitant with a significant reduction in B (insulin) cell volume to approximately 60% of normal. This reflects a pattern of events that occurs in non-insulin dependent diabetes. An accompanying reduction in PP (pancreatic polypeptide) cell volumes supports our hypothesis that altering A and PP cell volumes could reflect differential gene expression in those cells in the adult in which glucagon and PP are co-localized.


Requirements for phosphorylation of MAP kinase during meiosis in Xenopus oocytes.
Mitogen-activated protein (MAP) kinases are activated in response to a variety of extracellular stimuli by phosphorylation on tyrosine and threonine residues. Xp42 is a Xenopus laevis MAP kinase that is activated during oocyte maturation. Modified forms of Xp42 that lacked enzymatic activity or either of the phosphorylation sites were expressed in Xenopus oocytes. When meiotic maturation was induced with progesterone, each mutant Xp42 was phosphorylated, indicating that at least one kinase was activated that can phosphorylate Xp42 on tyrosine and threonine. Phosphorylation of one residue is not strictly dependent on phosphorylation of the other.


Ethyl acetate fraction of the root of Rubia cordifolia L. inhibits keratinocyte proliferation in vitro and promotes keratinocyte differentiation in vivo: potential application for psoriasis treatment.
Psoriasis is a skin disease associated with hyperproliferation and aberrant differentiation of keratinocytes. Our previous studies have identified the root of Rubia cordifolia L. as a potent antiproliferative and apoptogenic agent in cultured HaCaT cells (IC(50) 1.4 microg/ml). In the present study, ethanolic extract of Radix Rubiae was fractioned sequentially with hexane, ethyl acetate (EA), n-butanol and water. EA fraction was found to possess most potent antiproliferative action on HaCaT cells (IC(50) 0.9 microg/ml). Mechanistic study revealed that EA fraction induced apoptosis on HaCaT cells, as it was capable of inducing apoptotic morphological changes. Annexin V-PI staining assay also demonstrated that EA fraction significantly augmented HaCaT apoptosis. In addition, EA fraction decreased mitochondrial membrane potential in a concentration- and time-dependent manner. The standardized EA fraction was formulated into topical gel and its keratinocyte-modulating action was tested on mouse tail model. EA fraction dose-dependently increased the number and thickness of granular layer and epidermal thickness on mouse tail skin, indicative of the keratinocyte differentiation-inducing activity. Taking the in vitro and in vivo findings together, the present preclinical study confirms that EA fraction is a promising antipsoriatic agent warranting further development for psoriasis treatment.


Public health authorities race to contain fast-moving Zika outbreak.
With the Zika virus disease spreading rapidly through Latin America, public health authorities in the United States are racing to contain the outbreak. By the end of February, the CDC had confirmed 147 Zika cases in U.S. residents who had traveled to Zika-endemic areas. While symptoms of Zika tend to be mild, the virus has been linked to serious birth defects, so public health efforts are focused primarily at mitigating the risk Zika poses to pregnant women. By mid-February, nine pregnant women who had traveled to Zika-endemic areas and contracted the virus had been reported to the CDC. Of these, four pregnancies ended in miscarriage or termination, and one child was born with microcephaly. While Zika is transmitted primarily via mosquito bites, the CDC is investigating more than a dozen reported cases of Zika transmitted via sexual contact. Public health authorities say Zika can trigger Guillain-Barre syndrome in a small number of infections. For frontline clinicians, travel history is key to identifying potential cases of Zika in pregnant women who may have been exposed. The FDA has expedited approval of a new test that can detect antibodies to Zika. The CDC is in the process of providing the test to labs across the country, with a priority on public health departments.


Live lactate dehydrogenase-elevating virus (LDV) induces suppressor T cells that inhibit the development of delayed hypersensitivity to LDV.
A strong delayed-type hypersensitivity (DTH) response to lactate dehydrogenase-elevating virus (LDV) in mice was induced by immunization with u.v.- or heat-inactivated virus by the intravenous, intraperitoneal and especially the subcutaneous route. The peak DTH response was seen 7 days after immunization. Live virus, in contrast, did not induce a DTH response in young (1- to 3-month-old) mice irrespective of inoculation route, except after pretreatment with cyclophosphamide (CY), when the response peaked at 14 days. Live virus, however, induced a significant DTH response in old mice (greater than 8 months) without CY. The DTH response to inactivated virus was reduced when live virus was given intraperitoneally at the same time, but was partially restored when Ia-positive peritoneal cells were also given intravenously. The DTH response induced in infected mice pretreated with CY was suppressed by injection of spleen cells from infected or from normal 1- to 3-month-old mice. Suppression by normal spleen cells was abolished by treatment with anti-Thy1.2, anti-Lyt1 and anti-Lyt2 plus complement, whereas suppression by spleen cells from infected mice was prevented by anti-Thy1.2 and anti-Lyt2 plus complement. It is concluded that suppression of the DTH response was associated with induction of suppressor T cells and that severe depletion of Ia-positive cells may also have played a part.


The strides to reduce salt intake in Brazil: have we done enough?
Non-communicable chronic diseases (NCDs) are a major cause of morbidity and mortality in Brazil and inadequate diet is an important risk factor. Among the NCDs, cardiovascular diseases are very prevalent and sodium reduction in the population is a priority of health sector, because Brazilians consume more than twice the daily World Health Organization (WHO) sodium recommendation. Taking into account that sodium sources vary in the country among different age and income groups, several strategies are needed in order to reduce sodium intake, as consumer education, food reformulation, health promotion in school and work settings, food regulation and healthcare initiatives. So far, since 2011, the first results of sodium targets for processed foods and healthcare improvements are promising, and bring lessons that can be helpful for other countries. Nevertheless, more efforts on communication for healthy behaviors, food regulation, engagement of other partners and stakeholders and improving the monitoring system are key to advance in reducing sodium consumption from 4,700 to 2,000 mg per day until 2020.


Improving Video Segmentation by Fusing Depth Cues and the Visual Background Extractor (ViBe) Algorithm.
Depth-sensing technology has led to broad applications of inexpensive depth cameras that can capture human motion and scenes in three-dimensional space. Background subtraction algorithms can be improved by fusing color and depth cues, thereby allowing many issues encountered in classical color segmentation to be solved. In this paper, we propose a new fusion method that combines depth and color information for foreground segmentation based on an advanced color-based algorithm. First, a background model and a depth model are developed. Then, based on these models, we propose a new updating strategy that can eliminate ghosting and black shadows almost completely. Extensive experiments have been performed to compare the proposed algorithm with other, conventional RGB-D (Red-Green-Blue and Depth) algorithms. The experimental results suggest that our method extracts foregrounds with higher effectiveness and efficiency.


Tunable order-disorder continuum in protein-DNA interactions.
DNA-binding protein domains (DBDs) sample diverse conformations in equilibrium facilitating the search and recognition of specific sites on DNA over millions of energetically degenerate competing sites. We hypothesize that DBDs have co-evolved to sense and exploit the strong electric potential from the array of negatively charged phosphate groups on DNA. We test our hypothesis by employing the intrinsically disordered DBD of cytidine repressor (CytR) as a model system. CytR displays a graded increase in structure, stability and folding rate on increasing the osmolarity of the solution that mimics the non-specific screening by DNA phosphates. Electrostatic calculations and an Ising-like statistical mechanical model predict that CytR exhibits features of an electric potential sensor modulating its dimensions and landscape in a unique distance-dependent manner, while DNA plays the role of a non-specific macromolecular chaperone. Accordingly, CytR binds its natural half-site faster than the diffusion-controlled limit and even random DNA conforming to an electrostatic-steering binding mechanism. Our work unravels for the first time the synergistic features of a natural electrostatic potential sensor, a novel binding mechanism driven by electrostatic frustration and disorder, and the role of DNA in promoting distance-dependent protein structural transitions critical for switching between specific and non-specific DNA-binding modes.


The Amazon River plume, a barrier to animal dispersal in the Western Tropical Atlantic.
The dispersal of marine organisms can be restricted by a set of isolation mechanisms including hard barriers or hydrological features. In the Western Atlantic Ocean, the Amazon River discharge has been shown to act as a biogeographical barrier responsible for the differences in reef fish communities between Caribbean Sea and Northeast Brazil continental shelves. Here, we compare the diversity of all Animalia phyla from biogeographic ecoregions along the Tropical Western Atlantic continental shelf to test the hypothesis that the Amazon River plume spatially structures species diversity. For that, we used beta diversity estimators and multivariate ecological analysis on a database of species occurrence of the whole animal kingdom including 175,477 occurrences of 8,375 species from six ecoregions along the Western Tropical Atlantic. Results of the whole animal kingdom and the richest phyla showed that the Caribbean Sea and Tropical Brazil ecoregions are isolated by the Amazon River Plume, broadening and confirming the hypothesis that it acts as a soft barrier to animal dispersal in the Western Tropical Atlantic. Species sharing is larger northwestwards, in direction of the Caribbean than the opposite direction. Beyond species isolation due to local characteristics such as low salinity and high turbidity, our results suggest the dominant northwestward currents probably play a major role in animal dispersion: it enhances the flux of larvae and other planktonic organisms with reduced mobility from Brazil to Caribbean and hinders their contrary movement. Thus, the Amazon area is a strong barrier for taxa with reduced dispersal capacity, while species of pelagic taxa with active swimming may transpose it more easily.


Vitamin D and Its Metabolites Deficiency in Acute Coronary Syndrome Patients Undergoing Coronary Angiography: A Case-Control Study.
Vitamin D deficiency is considered an emerging health problem that affects at least one billion patients worldwide. Calcitriol 1,25(OH)2D3 has several systemic effects, including anti-inflammatory, anti-thrombotic and anti-atherosclerotic impacts that explain its cardioprotective effects. The precise association between vitamin D and its metabolites and the value of supplements in acute coronary syndrome (ACS) is still controversial. This study aims to search the association between vitamin D2, D3, and metabolites and ACS in patients undergoing coronary angiography. This was a case-control study on 73 consecutive adult patients with ACS undergoing coronary angiography compared to 50 controls without coronary artery disease and matched for age and sex from June 2019 till July 2019. Echocardiography and coronary angiography were done for all cases. Plasma vitamin D and its metabolites were measured at admission for all participants along with chemistry profiles. Vitamin D and its metabolites were statistically significantly lower in ACS patients than the controls. Multivariate regression analysis revealed that low levels of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) significantly predicted ACS occurrence; the other significant predictors were high systolic blood pressure (BP), high total cholesterol, and low high-density lipoprotein-cholesterol. Interestingly, vitamin D2 and D3 did not significantly predict ACS (p>0.05). We did not find a statistically significant association between the number of affected coronary vessels and vitamin D metabolites. Moreover, there was no statistically significant correlation between vitamin D and its metabolites and left ventricular ejection fraction measured by echocardiography. There was a strong association between vitamin D and all its metabolites with ACS. Significantly, low 25(OH)D and 1,25(OH)2D predicted ACS, but vitamin D2 and D3 did not. Large randomized controlled trials are needed to verify the beneficial values of vitamin D supplementation in ACS patients.


Influence of oxygenated organic aerosols (OOAs) on the oxidative potential of diesel and biodiesel particulate matter.
Generally, the magnitude of pollutant emissions from diesel engines running on biodiesel fuel is ultimately coupled to the structure of the fuel's constituent molecules. Previous studies demonstrated the relationship between the organic fraction of particulate matter (PM) and its oxidative potential. Herein, emissions from a diesel engine running on different biofuels were analyzed in more detail to explore the role that different organic fractions play in the measured oxidative potential. In this work, a more detailed chemical analysis of biofuel PM was undertaken using a compact time of flight aerosol mass spectrometer (c-ToF AMS). This enabled a better identification of the different organic fractions that contribute to the overall measured oxidative potentials. The concentration of reactive oxygen species (ROS) was measured using a profluorescent nitroxide molecular probe 9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-ethynyl)-10-(phenylethynyl)anthracene (BPEAnit). Therefore, the oxidative potential of the PM, measured through the ROS content, although proportional to the total organic content in certain cases, shows a much higher correlation with the oxygenated organic fraction as measured by the c-ToF AMS. This highlights the importance of knowing the surface chemistry of particles for assessing their health impacts. It also sheds light onto new aspects of particulate emissions that should be taken into account when establishing relevant metrics for assessing health implications of replacing diesel with alternative fuels.


Novel protocols for P300-based brain-computer interfaces.
The oddball protocol is often used in brain-computer interfaces (BCIs) to induce P300 ERPs, although, recently, some issues have been shown to detrimentally effect its performance. In this paper, we study a new periodic protocol and explore whether it can compete with the standard oddball protocol within the context of a BCI mouse. We found that the new protocol consistently and significantly outperforms the standard oddball protocol in relation to information transfer rates (33 bits/min for the former and 22 bits/min for the latter, measured at 90% accuracy) as well as P300 amplitudes. Furthermore, we performed a comparison of two periodic protocols with two less conventional oddball-like protocols that reveals the importance of the interactions between task and sequence in determining the success of a protocol.


Measuring Mental Workload with EEG+fNIRS.
We studied the capability of a Hybrid functional neuroimaging technique to quantify human mental workload (MWL). We have used electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) as imaging modalities with 17 healthy subjects performing the letter n-back task, a standard experimental paradigm related to working memory (WM). The level of MWL was parametrically changed by variation of n from 0 to 3. Nineteen EEG channels were covering the whole-head and 19 fNIRS channels were located on the forehead to cover the most dominant brain region involved in WM. Grand block averaging of recorded signals revealed specific behaviors of oxygenated-hemoglobin level during changes in the level of MWL. A machine learning approach has been utilized for detection of the level of MWL. We extracted different features from EEG, fNIRS, and EEG+fNIRS signals as the biomarkers of MWL and fed them to a linear support vector machine (SVM) as train and test sets. These features were selected based on their sensitivity to the changes in the level of MWL according to the literature. We introduced a new category of features within fNIRS and EEG+fNIRS systems. In addition, the performance level of each feature category was systematically assessed. We also assessed the effect of number of features and window size in classification performance. SVM classifier used in order to discriminate between different combinations of cognitive states from binary- and multi-class states. In addition to the cross-validated performance level of the classifier other metrics such as sensitivity, specificity, and predictive values were calculated for a comprehensive assessment of the classification system. The Hybrid (EEG+fNIRS) system had an accuracy that was significantly higher than that of either EEG or fNIRS. Our results suggest that EEG+fNIRS features combined with a classifier are capable of robustly discriminating among various levels of MWL. Results suggest that EEG+fNIRS should be preferred to only EEG or fNIRS, in developing passive BCIs and other applications which need to monitor users' MWL.


Ruptured submucosal gastric artery microaneurysm.
A patient with massive upper gastrointestinal hemorrhage from a ruptured submucosal gastric artery microaneurysm is described. Intraoperative diagnosis was made and wedge resection of the lesion resulted in survival of the patient. Forty-two cases in this entity have been reported in the literature, with nonoperative therapy being uniformly fatal; there were only four cases of successful surgical management. An increased awareness of this entity in cases of unexplained gastrointestinal hemorrhage is the key to diagnosis and successful management.


Infrequent and low AIRE expression in thymoma: difference in AIRE expression among WHO subtypes does not correlate with association of MG.
Thymoma is frequently associated with autoimmune diseases, including myasthenia gravis (MG). The failure of thymoma microenvironment to induce T cell tolerance may be responsible for its association of MG. Autoimmune regulator (AIRE) expression in the medullary thymic epithelial cells has been reported to play a role in presenting autoantigen and induction of tolerance. We studied AIRE mRNA in 45 thymomas and three normal thymi using quantitative reverse transcription polymerase chain reaction (RT-PCR). Only 23/45 (51.1%) of thymomas expressed AIRE mRNA at low levels while all normal thymi expressed AIRE mRNA. There was no correlation between AIRE mRNA and association of MG or presence of anti-acetylcholine receptor antibody. The infrequent and low expression of AIRE mRNA may play a role the induction of autoimmune diseases but other factors also seem to be involved.


The Impact of Midurethral Sling Surgery on Sexual Activity and Function in Women With Stress Urinary Incontinence.
Stress urinary incontinence has a negative impact on sexual function. To assess the effect of midurethral sling surgery on sexual activity and function in women with stress urinary incontinence. This is a secondary analysis of the Value of Urodynamics Prior to Stress Incontinence Surgery (VUSIS-II) study, which assessed the value of urodynamics in women with (predominantly) stress urinary incontinence. Patients who underwent retropubic or transobturator sling surgery were included in the present study if information was available on sexual activity before and 12 months after surgery. Data were collected from a self-report validated questionnaire combined with non-validated questions. The association between midurethral sling surgery and sexual function (coital incontinence, satisfaction, and dyspareunia) was compared with McNemar χ(2) tests for nominal data and paired t-tests for ordinal data. Potentially influential factors were analyzed with univariable and multivariable logistic regression analyses. Changes in sexual activity and sexual function after midurethral sling surgery. Information on sexual activity was available in 293 of the 578 women (51%) included in the VUSIS-II study. At baseline, 252 of 293 patients (86%) were sexually active vs 244 of 293 (83%) after 12 months. More patients with cured stress urinary incontinence were sexually active postoperatively (213 of 247 [86%] vs 31 of 46 [67%], P < .01). There was a significant decrease in coital incontinence (120 of 236 [51%] preoperatively vs 16 of 236 [7%] postoperatively, P < .01). De novo dyspareunia was present in 21 of 238 women (9%). There was a greater improvement in coital incontinence after placement of the retropubic sling compared with the transobturator sling (odds ratio = 2.04, 95% CI = 1.10-3.80, P = .02). These data show that midurethral sling surgery has an overall positive influence on sexual function in women with stress urinary incontinence. The retropubic sling is more effective than the transobturator sling for improvement of coital incontinence. De novo dyspareunia was present in 1 of 11 women.


Haplodeficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function.
Cardiac fibrosis (CF), a repairing process following myocardial infarction (MI), is characterized by abnormal proliferation of cardiac fibroblasts and excessive deposition of extracellular matrix (ECM) resulting in inevitable resultant heart failure. TGF-β (transforming growth factor-β)/ALK5 (Activin receptor-like kinase 5)/Smad2/3/4 pathways have been reported to be involved in the process. Recent studies have implicated both activin and its specific downstream component ALK4 in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 is upregulated in the pressure-overloaded heart and its partial inhibition attenuated the pressure overload-induced CF and cardiac dysfunction. However, the role of ALK4 in the pathogenesis of MI-induced CF, which is usually more severe than that induced by pressure-overload, remains unknown. Here we report: 1) In a wild-type mouse model of MI, ALK4 upregulation was restricted in the fibroblasts of the infarct border zone; 2) In contrast, ALK4+/- mice with a haplodeficiency of ALK4 gene, showed a significantly attenuated CF in the border zone, with a smaller scar size, a preserved cardiac function and an improved survival rate post-MI; 3) Similarly to pressure-overloaded heart, these beneficial effects might be through a partial inactivation of the Smad3/4 pathway but not MAPK cascades; 4) The apoptotic rate of the cardiomyocytes were indistinguishable in the border zone of the wild-type control and ALK4+/- mice; 5) Cardiac fibroblasts isolated from ALK4+/- mice showed reduced migration, proliferation and ECM synthesis in response to hypoxia. These results indicate that partial inhibition of ALK4 may reduce MI-induced CF, suggesting ALK4 as a novel target for inhibition of unfavorable CF and for preservation of LV systolic function induced by not only pressure-overload but also MI.


Merkel-cell carcinoma: preoperative clinical diagnosis and therapeutic implications.
The authors report the personal experience of some patients undergoing surgery for carcinoma of Merkel and discuss the diagnosis and therapeutic approach guided by literature and international guidelines. Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumour, which prefers the Caucasian race in adulthood. Approximately 78% of patients are over than 59 years, the most common location is at the level of the head and neck (50.8%) and less frequently in the limbs (33.7%). The literature is discordant about the causes and risk factors for this cancer. In fact, some authors describe major risk factor the immunosoppression, still others see prolonged exposition to UV radiation increases the risk for the onset of this tumor. Metastasizes early to the skin (28%), the lymph nodes (27%), liver (13%), lung (10%), bone (10%) and encephalon (6%), and may recur both locally (30-60%) and both locoregional (40-73%). Our experience confirms the difficulty of preoperative clinical diagnosis and a correct therapeutic approach to Merkel cell carcinoma for the lack of specific characteristics as first clinical assessment, which may keep the suspect nature. International guidelines provide a wide excision (3 cm in largeness and 2 cm in depth) to reduce the risk of disease recurrence, preferring adjuvant chemotherapy not radiotherapy. For lesions of stage I-II over the wide excision also regional lymphadenectomy is performed or, more rarely, the technique of sentinel lymph node.


Changes in Fatigue and Cognition in Patients with Relapsing Forms of Multiple Sclerosis Treated with Natalizumab: The ENER-G Study.
Fatigue and cognitive impairment are debilitating features of multiple sclerosis (MS). ENER-G was a 12-month, open-label, multicenter, single-arm observational study designed to evaluate changes in fatigue and cognition in MS patients treated with natalizumab. Adults with relapsing MS and initiating natalizumab were enrolled. The primary endpoint was change in Visual Analog Scale for Fatigue (VAS-F) score over 12 weeks. Changes in Modified Fatigue Impact Scale (MFIS) score, Fatigue Severity Scale (FSS) score, and cognitive performance, using Automated Neuropsychological Assessment Metrics (ANAM), were also assessed. Patients (N = 89) had a mean age of 41 years and a median Expanded Disability Status Scale score of 3.0, and 83% had used at least two prior MS therapies. Significant improvements were observed and maintained at 12 weeks in VAS-F (mean ± SD baseline score, 77.7 ± 10.2; mean ± SD change, -14.9 ± 17.1; P < .0001), MFIS (mean baseline score, 59.1 ± 12.2; mean change, -7.4 ± 11.8; P < .0001), and FSS (median baseline score, 6.3 [range, 3.9-7.0]; median change, -0.4 [range, -2.9-1.4]; P < .0001). Cognitive performance remained stable or improved (depending on the ANAM measure). Thus significant improvements in fatigue were maintained over time, and cognitive performance improved or remained stable up to 48 weeks after initiation of natalizumab in MS patients with some degree of fatigue.


The effects of partial uncoupling upon the kinetics of ATP synthesis by vesicles from Paracoccus denitrificans and by bovine heart submitochondrial particles. Implications for the mechanism of the proton-translocating ATP synthase.
1. Reduction in the magnitude of the respiration-dependent protonmotive force (proton electrochemical gradient in mV) of vesicles from Paracoccus denitrificans, and of submitochondrial particles, has been found to be paralleled small increases in S50% values for both ADP and Pi. For example, reduction of the protonmotive force of P. denitrificans vesicles from 145 mV to 110 mV was accompanied by an increase of S50% (ADP) from 8 microM to 18 microM, and an increase of S50% (Pi) from 0.33 mM to 1.4 mM. This result was obtained with partial uncoupling quantities of both carbonyl-cyanide p-trifluoromethoxyphenylhydrazone and of the synergistic combination of nigericin plus valinomycin in the presence of K+. In view of the similar effects of these two different methods of uncoupling it is concluded that the changes in S50% were a consequence of the diminished protonmotive force acting on the ATP synthase rather than of a secondary, direct interaction of the uncouplers with the enzyme. Changes in S50% rather than Km are described because under several sets of conditions double-reciprocal plots were nonlinear. 2. For equivalent attenuations in the rate of ATP synthesis by submitochondrial particles, 2,4-dinitrophenol caused much larger increases in S50% (ATP) than did carbonylcyanide p-trifluoromethoxyphenylhydrazone. Therefore it is concluded that the effect of 2,4-dinitrophenol was primarily a consequence of its previously recognized direct interaction with the F1 segment of the mitochondrial ATPase. The concentration range of 2,4-dinitrophenol that raised S50% (ADP) is similar to that which weakens the binding of ADP to a particular type of site on the purified F1 sector of ATP synthase. This correlation is consistent with such a site having a catalytic role during ATP synthesis. 3. A titration of the rate of ATP synthesis by vesicles of P. denitrificans with increasing quantities of carbonylcyanide p-trifluoromethoxyphenylhydrazone showed that the initial titres of the uncoupler caused large decreases in the rate of ATP synthesis for relatively small attenuations in the protonmotive force. Thus the initial 20 mV drop in the protonmotive force was accompanied by a reduction of more than 65% in the rate of ATP synthesis. Over the lowest range of values of protonmotive force that drove detectable rates of ATP synthesis however, the dependence of the rate was a less steep function of the protonmotive force. A plot of the logarithm of the rate of ATP synthesis against protonmotive force reveals a biphasic relationship. There does not appear to be a 'threshold' value of the protonmotive force below which ATP synthesis is blocked by kinetic factors. 4. The relationships of the protonmotive force with S50% values and with the rate of ATP synthesis (at near saturating concentrations of ADP and Pi) are discussed in relation to possible mechanisms for the coupling of proton translocation to ATP synthesis.


GSNFS: Gene subnetwork biomarker identification of lung cancer expression data.
Gene expression has been used to identify disease gene biomarkers, but there are ongoing challenges. Single gene or gene-set biomarkers are inadequate to provide sufficient understanding of complex disease mechanisms and the relationship among those genes. Network-based methods have thus been considered for inferring the interaction within a group of genes to further study the disease mechanism. Recently, the Gene-Network-based Feature Set (GNFS), which is capable of handling case-control and multiclass expression for gene biomarker identification, has been proposed, partly taking into account of network topology. However, its performance relies on a greedy search for building subnetworks and thus requires further improvement. In this work, we establish a new approach named Gene Sub-Network-based Feature Selection (GSNFS) by implementing the GNFS framework with two proposed searching and scoring algorithms, namely gene-set-based (GS) search and parent-node-based (PN) search, to identify subnetworks. An additional dataset is used to validate the results. The two proposed searching algorithms of the GSNFS method for subnetwork expansion are concerned with the degree of connectivity and the scoring scheme for building subnetworks and their topology. For each iteration of expansion, the neighbour genes of a current subnetwork, whose expression data improved the overall subnetwork score, is recruited. While the GS search calculated the subnetwork score using an activity score of a current subnetwork and the gene expression values of its neighbours, the PN search uses the expression value of the corresponding parent of each neighbour gene. Four lung cancer expression datasets were used for subnetwork identification. In addition, using pathway data and protein-protein interaction as network data in order to consider the interaction among significant genes were discussed. Classification was performed to compare the performance of the identified gene subnetworks with three subnetwork identification algorithms. The two searching algorithms resulted in better classification and gene/gene-set agreement compared to the original greedy search of the GNFS method. The identified lung cancer subnetwork using the proposed searching algorithm resulted in an improvement of the cross-dataset validation and an increase in the consistency of findings between two independent datasets. The homogeneity measurement of the datasets was conducted to assess dataset compatibility in cross-dataset validation. The lung cancer dataset with higher homogeneity showed a better result when using the GS search while the dataset with low homogeneity showed a better result when using the PN search. The 10-fold cross-dataset validation on the independent lung cancer datasets showed higher classification performance of the proposed algorithms when compared with the greedy search in the original GNFS method. The proposed searching algorithms provide a higher number of genes in the subnetwork expansion step than the greedy algorithm. As a result, the performance of the subnetworks identified from the GSNFS method was improved in terms of classification performance and gene/gene-set level agreement depending on the homogeneity of the datasets used in the analysis. Some common genes obtained from the four datasets using different searching algorithms are genes known to play a role in lung cancer. The improvement of classification performance and the gene/gene-set level agreement, and the biological relevance indicated the effectiveness of the GSNFS method for gene subnetwork identification using expression data.


Pediatric Gastroesophageal Reflux Disease: Systematic Review on Prognosis and Prognostic Factors.
In this systematic review, we summarize the evidence on prognosis and prognostic factors of pediatric gastroesophageal reflux disease (GERD). A structured search of Embase and MEDLINE/PubMed (inception to April 2016) yielded 5365 references; 4 publications met our inclusion criteria (risk of bias moderate-high). Definitions and outcome measures varied widely between studies. The percentage of children with a diagnosis of GERD with esophagitis that had persisting symptoms and/or were on antireflux medication at follow-up (12 months to >5 years) ranged from 23% (weekly symptoms) to 68% (antireflux medication), depending on definition used. In children with a diagnosis of GERD without esophagitis, 1.4% developed esophagitis at follow-up (>5 years); none developed Barrett esophagus. In conclusion, prognostic studies on pediatric GERD are of limited quality and show large methodological heterogeneity. Based on these studies, we are unable to identify those children at risk for unfavorable outcome with regards to GERD symptoms or endoscopic complications.