A novel approach to therapeutic angiogenesis for patients with critical limb ischemia by sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel: an initial report of the phase I-IIa study.
Limb ischemia remains a challenge. To overcome shortcomings or limitations of gene therapy or cell transplantation, a sustained release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel has been developed. A phase I-IIa study was performed, in which 7 patients had critical limb ischemia. They were intramuscularly injected with 200 microg of bFGF-incorporated gelatin hydrogel microspheres into the gastrocnemius of the ischemic limb. End-points were safety and feasibility of treatment after 4 and 24 weeks. One patient was excluded from the study for social reasons, but only after symptomatic improvements. In the evaluation of the other 6 patients, significant improvements were observed in the distance walked in 6 min (295+/-42 m vs 491+/-85 m for pretreatment vs after 24 weeks, p=0.023) and in transcutaneous oxygen pressure (53.5+/-5.2 mmHg vs 65.5+/-4.0 mmHg, p=0.03). The rest pain scale also improved (3.5+/-0.2 vs 1.0+/-0.6, p=0.022). The ankle-brachial pressure index improved at 4 weeks but not at 24 weeks. Among 5 patients who had a non-healing foot ulcer, the ulcer was completely healed in 3 patients, reduced in 1, and there was no change in 1 patient at 24 weeks. The blood levels of bFGF were undetected or within the normal level in all patients. The sustained release of bFGF from gelatin hydrogel might be simple, safe, and effective to achieve therapeutic angiogenesis because it did not need genetic materials or collection of implanted cells, and because it did not have any general effects, which was supported by there being no elevation of the bFGF serum level.


Oxygenation of arachidonoyl lysophospholipids by lipoxygenases from soybean, porcine leukocyte, or rabbit reticulocyte.
Oxygenation of arachidonoyl lysophosphatidylcholine (lysoPC) or arachidonoyl lysophosphatidic acid (lysoPA) by lipoxygenase (LOX) was examined. The oxidized products were identified by HPLC/UV spectrophotometry/mass spectrometry analyses. Straight-phase and chiral-phase HPLC analyses indicated that soybean LOX-1 and rabbit reticulocyte LOX oxygenated arachidonoyl lysophospholipids mainly at C-15 with the S form as major enantiomer, whereas porcine leukocyte LOX oxygenated at C-12 with the S form. Next, the sequential exposure of arachidonoyl-lysoPC to soybean LOX-1 and porcine leukocyte LOX afforded two major isomers of dihydroxy derivatives with conjugated triene structure, suggesting that 15(S)-hydroperoxyeicosatetraenoyl derivatives were converted to 8,15(S)-dihydroxyeicosatetraenoyl derivatives. Separately, arachidonoyl-lysoPA, but not arachidonoyl-lysoPC, was found to be susceptible to double oxygenation by soybean LOX-1 to generate a dihydroperoxyeicosatetraenoyl derivative. Overall, arachidonoyl lysophospholipids were more efficient than arachidonic acid as LOX substrate. Moreover, the catalytic efficiency of arachidonoyl-lysoPC as substrate of three lipoxygenases was much greater than that of arachidonoyl-lysoPA or arachidonic acid. Taken together, it is proposed that arachidonoyl-lysoPC or arachidonoyl-lysoPA is efficiently oxygenated by plant or animal lipoxygenases, C12- or C15-specific, to generate oxidized products with conjugated diene or triene structure.


Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity.
In 2007, the International Agency for Research on Cancer presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. Although these findings imply vigorous local carcinogen metabolism, little is known about levels and distribution of phase I, II, and III (drug egress) enzymes in human oral mucosa. In this study here, we integrated clinical data, and imaging and histopathologic analyses of an oral squamous cell carcinoma that arose at the site of smokeless tobacco quid placement in a patient. Immunoblot and immunohistochemical (IHC) analyses were used to identify tumor and normal human oral mucosal smokeless tobacco-associated metabolic activation and detoxification enzymes. Human oral epithelium contains every known phase I enzyme associated with nitrosamine oxidative bioactivation with approximately 2-fold interdonor differences in protein levels. Previous studies have confirmed approximately 3.5-fold interdonor variations in intraepithelial phase II enzymes. Unlike the superficially located enzymes in nonreplicating esophageal surface epithelium, IHC studies confirmed that oral mucosal nitrosamine metabolizing enzymes reside in the basilar and suprabasilar region, which notably is the site of ongoing keratinocyte DNA replication. Clearly, variations in product composition, nitrosamine metabolism, and exposure duration will modulate clinical outcomes. The data presented here form a coherent picture consistent with the abundant experimental data that link tobacco-specific nitrosamines to human oral cancer.


Modeling of finite amplitude acoustic waves in closed cavities using the Galerkin method.
Nonlinear resonant gas oscillations in closed ducts are investigated by solving a previously derived, quasi-one-dimensional, nonlinear wave equation that accounts for forcing, gas dynamic nonlinearities, and viscous dissipation. This equation is solved with the approximate Galerkin method to determine the dependence of driven oscillations upon the duct shape, forcing frequency, and forcing amplitude. Initially, the applicability of the developed Galerkin solution approach was studied by investigating oscillations in a straight duct, closed at both ends and periodically oscillated at a single frequency. It is shown that the Galerkin method predictions of shock wave-like oscillations in such ducts are in excellent agreement with results obtained with other numerical solution techniques. Next, this study investigated the forced response of a class of horn-shaped ducts, and it is shown that for a given forcing amplitude, there exists a nonmonotonic increase in compression ratio as the duct's flare constant is increased. Finally, it is shown that oscillations driven in ducts whose shapes were chosen to provide shifting of the second and third natural acoustic mode frequencies exhibit significant waveform distortion and non-negligible increases in compression ratio when compared with oscillations driven in straight ducts.


Upper airway stimulation for obstructive sleep apnea-Can radiological position monitoring predict tongue motion one year after implantation?
Tongue motion patterns (TMP) can influence the outcome of upper airway stimulation (UAS) in the treatment of obstructive sleep apnea (OSA). As a postoperative control, the cuff position of the stimulation lead is monitored via X‑ray imaging. A multidimensional X‑ray assessment system was established and the association between these positional assessments and TMP was investigated 1 year after implantation. The study on TMP and the X‑ray assessments were carried out at a German ear nose and throat clinic as an implantation center. The TMPs were assessed under bipolar electrode configuration and were categorized according to the currently available literature as right-sided protrusion (RP), left-sided protrusion (LP), bilateral protrusion (BP) and mixed activation (MA). The X‑ray assessment was carried out in five dimensions: the position relative to the mandible and hyoid, cuff steepness in the lateral view of the neck, the cuff position based on the single electrode, and the lead connection to the cuff in the anterior-posterior view. The analyses were performed by three raters with different medical backgrounds and knowledge regarding TMP. In approximately 60% of patients, the apnea-hypopnea index was reduced to below 15/h 1 year after implantation. The most common TMPs were RP and BP (82.9%). The interrater variability of the X‑ray assessment was good except for one category. Furthermore, no relevant associations were found apart from the correlation between a favorable TMP and the cuff position with respect to the lateral position of the stimulation cable. Despite good interrater variability and convenient usage of the suggested X‑ray assessment system, this approach did not enable the identification of any associations by which a TM and, therefore, a possible straightforward or complicated treatment pathway could be predicted. Attention should possibly be paid to a rotation of the cuff during implantation with a lateral position of the stimulation lead.


High-Order Local Pooling and Encoding Gaussians Over a Dictionary of Gaussians.
Local pooling (LP) in configuration (feature) space proposed by Boureau et al. explicitly restricts similar features to be aggregated, which can preserve as much discriminative information as possible. At the time it appeared, this method combined with sparse coding achieved competitive classification results with only a small dictionary. However, its performance lags far behind the state-of-the-art results as only the zero-order information is exploited. Inspired by the success of high-order statistical information in existing advanced feature coding or pooling methods, we make an attempt to address the limitation of LP. To this end, we present a novel method called high-order LP (HO-LP) to leverage the information higher than the zero-order one. Our idea is intuitively simple: we compute the first- and second-order statistics per configuration bin and model them as a Gaussian. Accordingly, we employ a collection of Gaussians as visual words to represent the universal probability distribution of features from all classes. Our problem is naturally formulated as encoding Gaussians over a dictionary of Gaussians as visual words. This problem, however, is challenging since the space of Gaussians is not a Euclidean space but forms a Riemannian manifold. We address this challenge by mapping Gaussians into the Euclidean space, which enables us to perform coding with common Euclidean operations rather than complex and often expensive Riemannian operations. Our HO-LP preserves the advantages of the original LP: pooling only similar features and using a small dictionary. Meanwhile, it achieves very promising performance on standard benchmarks, with either conventional, hand-engineered features or deep learning-based features.


Stress distribution within rotator cuff tendons with a crescent-shaped and an L-shaped tear.
There are 2 representative shapes of full-thickness rotator cuff tears commonly observed: crescent-shaped and L-shaped tears. To date, the exact process of tear propagation in each shape remains unknown. To determine the stress distribution pattern in rotator cuff tendons with a crescent-shaped tear and an L-shaped tear. Descriptive laboratory study. The computed tomography (CT) data of a normal cadaveric shoulder from a 69-year-old man were used to develop a 3-dimensional finite element model of the rotator cuff tendons. Three different sizes (1.0-, 2.0-, and 3.0-cm widths) of crescent-shaped and L-shaped tears were created. Tensile load was applied to each cuff tendon that simulated shoulder abduction and external rotation in the hanging-arm position. Elastic analysis was performed, and distribution of the von Mises equivalent stress was calculated. Then, the stress distribution pattern was compared between the 2 tear shapes and among the 3 different tear sizes. In the crescent-shaped tear models, stress concentration was seen in both the anterior and the posterior edges of the torn tendon stump. In the L-shaped tear models, stress concentration was seen in the posterior torn tendon edge as well as the bottom of the longitudinal tear. The areas with high stress concentration increased with increasing tear size. At the posterior torn tendon edge, a common site of delamination, the articular half represented a higher equivalent stress than the bursal half in all models. The highest equivalent stress increased with an increase in tear size for both the abduction and the external rotation loads. A high stress concentration was seen in both the anterior and the posterior tendon edge in crescent-shaped tears and in both the posterior tendon edge and the bottom of the longitudinal tear in L-shaped tears. Stress concentration inside the tendon increased with increasing tear size. Crescent-shaped tears may propagate in the anterior and posterior directions, whereas L-shaped tears may propagate in the posterior and medial directions. Tear propagation may accelerate with an increase in tear size.


Hyperkalemia and Treatment With RAAS Inhibitors During Acute Heart Failure Hospitalizations and Their Association With Mortality.
This study investigated associations between incident hyperkalemia during acute heart failure (HF) hospitalizations and changes in renin-angiotensin-aldosterone system (RAAS) inhibitors. Hyperkalemia is a potential complication of RAAS inhibitors. For patients with HF, fear of hyperkalemia may lead to failure to deliver guideline-recommended doses of RAAS inhibitors. Serum potassium concentrations were measured daily from baseline (<24 h after admission) until discharge or day 7 in 1,589 patients enrolled in the PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) trial. Incident hyperkalemia was defined as at least 1 episode of potassium >5.0 mEq/l. The primary outcome was all-cause mortality at 180 days. Overall, serum potassium concentrations increased from 4.3 ± 0.6 mEq/l at baseline to 4.5 ± 0.6 mEq/l at discharge or day 7 (p < 0.001). Patients developing incident hyperkalemia (n = 564; 35%) were more often taking mineralocorticoid antagonists (MRAs) therapy prior to hospitalization and were more likely to have them down-titrated during hospitalization, independent of confounders. Incident hyperkalemia was not associated with adverse outcomes. Yet, down-titration of MRAs during hospitalization was independently associated with 180-day mortality (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.15 to 2.60), regardless of incident hyperkalemia (pinteraction >0.10). Patients with incident hyperkalemia who were discharged with the same or increased dose of MRAs (HR: 0.52; 95% CI: 0.32 to 0.85) or angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (HR: 0.47; 95% CI: 0.29 to 0.77) had a lower 180-day mortality. Incident hyperkalemia is common in patients hospitalized for acute HF and is not associated with adverse outcomes. Incident hyperkalemia is associated with down-titration of MRAs, but patients who maintained or increased their dose of MRAs and/or ACE inhibitors/ARB during acute HF hospitalization had better 180-day survival.


The regulation of actin polymerization in differentiating U937 cells correlates with increased membrane levels of the pertussis-toxin-sensitive G-protein Gi2.
Undifferentiated U937 cells appear to lack a capacity of increase cellular F-actin. However, electropermeabilized cells gain the ability to respond in this way to a guanine nucleotide analogue, guanosine 5'-[gamma-thio]trisphosphate (GTP[S]) after 1 h of treatment with dibutyryl cyclic AMP (db-cAMP). The results reported here show that the levels of membrane association of the G-protein Gi2 alpha increase with a time course identical with that of the GTP[S]-sensitivity of electropermeabilized cells. These results suggest that Gi2 alpha may be involved in the signal-transduction pathway leading to actin polymerization in db-cAMP-differentiated U937 cells.


A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.
The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03<or=EC(50)<3 microM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics. The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome.


Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes.
Antibody genes are diversified by somatic hypermutation (SHM), gene conversion and class-switch recombination. All three processes are initiated by the activation-induced deaminase (AID). According to a DNA deamination model of SHM, AID converts cytosine to uracil in DNA sequences. The initial deamination of cytosine leads to mutation and recombination in pathways involving replication, DNA mismatch repair and possibly base excision repair. The DNA sequence context of mutation hotspots at G-C pairs during SHM is DGYW/WRCH (G-C is a hotspot position, R = A/G, Y = T/C, W = A/T, D = A/G/T). To investigate the mechanisms of AID-induced mutagenesis in a model system, we studied the genetic consequences of AID expression in yeast. We constructed a yeast vector with an artificially synthesized human AID gene insert using codons common to highly expressed yeast genes. We found that expression of the artificial hAIDSc gene was moderately mutagenic in a wild-type strain and highly mutagenic in an ung1 uracil-DNA glycosylase-deficient strain. A majority of mutations were at G-C pairs. In the ung1 strain, C-G to T-A transitions were found almost exclusively, while a mixture of transitions with 12% transversions was characteristic in the wild-type strain. In the ung1 strain mutations that could have originated from deamination of the transcribed stand were found more frequently. In the wild-type strain, the strand bias was reversed. DGYW/WRCH motifs were preferential sites of mutations. The results are consistent with the hypothesis that AID-mediated deamination of DNA is a major cause of mutations at G-C base pairs in immunoglobulin genes during SHM. The sequence contexts of mutations in yeast induced by AID and those of somatic mutations at G-C pairs in immunoglobulin genes are significantly similar. This indicates that the intrinsic substrate specificity of AID itself is a primary determinant of mutational hotspots at G-C base pairs during SHM.


Meridianin D analogues possess antibiofilm activity against Mycobacterium smegmatis.
The formation of bacterial biofilms significantly decreases the efficacy of antibiotic treatments. Herein, we've investigated the antibiofilm properties of the natural product meridianin D and a library of analogues against Mycobacterium smegmatis. As a result, we discovered several analogues that both inhibit and disperse M. smegmatis biofilms.


Annual Research Review: Parenting and children's brain development: the end of the beginning.
After questioning the practical significance of evidence that parenting influences brain development - while highlighting the scientific importance of such work for understanding how family experience shapes human development - this paper reviews evidence suggesting that brain structure and function are 'chiselled' by parenting. Although the generalisability of most findings is limited due to a disproportionate, but understandable focus on clinical samples (e.g., maltreated children with post-traumatic stress disorder (PTSD)) and causal inferences are difficult to draw because of the observational nature of most of the evidence, it is noteworthy that some work with community samples and very new experimental work (e.g., parent training) suggests that tentative conclusions regarding effects of parenting on the developing brain may well be substantiated in future research. Such efforts should focus on parenting in the normal range, experimental manipulations of parenting, differential susceptibility to parenting effects and pathway models linking parenting to brain development and, thereby, to behavioural development. Research on parenting and children's brain development may be regarded as at 'the end of the beginning'.


Magnetic composite biomaterials for tissue engineering.
Magnetic nanoparticles (MNPs) have been increasingly used in tissue engineering and regenerative medicine. These particles have been mainly employed as elements directly incorporated into cells or interacting with cell membranes; however, MNPs are now being combined with biomaterials to create other functionalities of the structural framework used to support cells, namely for controlling cellular responses and for enhancing drug delivery and release. This mini-review summarizes and highlights the latest developments and applications of polymeric/ceramic biomimetic scaffolds and hydrogels that contain MNPs for such purposes, also addressing future perspectives for the use of these magnetic composite biomaterials in biomedicine.


Plasma vitamin B-12 concentrations in an elderly latino population are predicted by serum gastrin concentrations and crystalline vitamin B-12 intake.
The prevalence of vitamin B-12 deficiency increases with age, probably resulting from malabsorption of food-bound B-12 secondary to gastric atrophy. On the basis of this assumption, the Institute of Medicine (IOM) recommends those aged >50 y consume crystalline vitamin B-12. There is limited information on the prevalence of gastric atrophy in the elderly and whether the IOM recommendation would be effective. The objective of this study was to assess predictors of vitamin B-12 status and their interactions in free-living elderly. Individuals (n = 57) with deficient plasma vitamin B-12 (p-B12 < 148 pmol/L) were compared with 68 individuals with marginal p-B12 (148-221 pmol/L) and 52 with normal p-B12 (>221 pmol/L) in a cross-sectional sample (n = 1546) of elderly (>60 y) Latinos in California. Associations were examined among p-B12 and serum gastrin, vitamin B-12 intake from food and crystalline sources, and medications that putatively affect vitamin B-12 absorption. Serum gastrin was elevated, indicating gastric atrophy, in 48% of participants with deficient p-B12, 23% with marginal p-B12 and 21% of normal p-B12 participants, and was a significant predictor of deficient p-B12 and high plasma homocysteine (p-tHcy). Median total vitamin B-12 intake exceeded recommendations and was similar among status groups. Crystalline vitamin B-12 intake in the normal p-B12 group was higher than in the deficient p-B12 group (P < 0.01), and tended to be higher than the marginal group (P = 0.07). When serum gastrin was elevated, p-B12 was predicted by crystalline vitamin B-12, but not by intake of vitamin B-12 from food. Elevated serum gastrin was highly prevalent and predicted vitamin B-12 depletion. Crystalline vitamin B-12 intake predicted p-B12 in individuals with elevated serum gastrin, supporting IOM recommendations to increase consumption of crystalline vitamin B-12.


Surveillance of vaccine-related adverse events in the first year of life: a Manitoba cohort study.
This study used data from the population database through which the province of Manitoba, Canada, administers its universal health insurance plan. Enrollment, hospitalization, and immunization files from children born in the 1987-1989 period were linked using the unique identification number assigned to each population member. Analysis of these linked data successfully identified serious potential adverse events in the first year of life and the timing of events around immunization. Not only is population-based active surveillance for immunization-related events feasible, but the techniques described, applied to years of data accumulated through surveillance, offer powerful research tools. Baseline population incidences of adverse events were calculated, temporal relationships between events and immunization assessed, and incidences for events showing true temporal associations determined. Eventual goals are the quantification of vaccine-related risk and the gathering of evidence concerning casual associations. The approach could be used readily by several other Canadian provinces and by health maintenance organizations in the United States.


Impact of sauropod dinosaurs on lagoonal substrates in the Broome Sandstone (Lower Cretaceous), Western Australia.
Existing knowledge of the tracks left by sauropod dinosaurs (loosely 'brontosaurs') is essentially two-dimensional, derived mainly from footprints exposed on bedding planes, but examples in the Broome Sandstone (Early Cretaceous) of Western Australia provide a complementary three-dimensional picture showing the extent to which walking sauropods could deform the ground beneath their feet. The patterns of deformation created by sauropods traversing thinly-stratified lagoonal deposits of the Broome Sandstone are unprecedented in their extent and structural complexity. The stacks of transmitted reliefs (underprints or ghost prints) beneath individual footfalls are nested into a hierarchy of deeper and more inclusive basins and troughs which eventually attain the size of minor tectonic features. Ultimately the sauropod track-makers deformed the substrate to such an extent that they remodelled the topography of the landscape they inhabited. Such patterns of substrate deformation are revealed by investigating fragmentary and eroded footprints, not by the conventional search for pristine footprints on intact bedding planes. For that reason it is not known whether similar patterns of substrate deformation might occur at sauropod track-sites elsewhere in the world.


Peak expiratory flow variability adjusted by forced expiratory volume in one second is a good index for airway responsiveness in asthmatics.
The lowest peak expiratory flow (PEF) over a week, expressed as a percentage of the highest PEF (Min%Max PEF) has been reported to be the index that most closely correlates with airway hyperresponsiveness (AHR) in asthmatics. However, both fluctuation of the airway caliber and airflow limitation are regarded as physiological properties of asthma closely related to AHR. An accurate index that shows the degree of AHR may be obtained by combining the index of airway lability with the parameters that represent airway caliber. Ninety-two steroid-naive and twenty-eight steroid-treated asthmatic patients were enrolled. Using the physiological parameters obtained from spirometry and PEF monitoring, we investigated the indices which correlate accurately with airway responsiveness measured by the inhalation challenge test. Although the methacholine threshold was related to all parameters that represent airway caliber and lability, Min%Max PEF had the strongest correlation with AHR. When Min%Max PEF was adjusted by the airway geometric factors, the normalization of Min%Max PEF with forced expiratory volume in one second as a percentage of the predicted value (%FEV(1)) improved the relationship between Min%Max PEF and AHR. Min%Max PEF adjusted by %FEV(1) showed a good correlation with airway responsiveness measured by the inhalation challenge test, and may be useful as a convenient alternative index of AHR in asthmatic patients.


Body Mass Index Is Associated with Impaired Semen Characteristics and Reduced Levels of Anti-Müllerian Hormone across a Wide Weight Range.
There is still controversy as to how body mass index (BMI) affects male reproduction. We investigated how BMI is associated with semen quality and reproductive hormones in 166 men, including 38 severely obese men. Standard semen analysis and sperm DNA integrity analysis were performed, and blood samples were analysed for reproductive hormones. Adjusted for age and time of abstinence, BMI was negatively associated with sperm concentration (B = -0.088, P = 0.009), total sperm count (B = -0.223, P = 0.001), progressive sperm motility (B = -0.675, P = 0.007), normal sperm morphology (B = -0.078, P = 0.001), and percentage of vital spermatozoa (B = -0.006, P = 0.027). A negative relationship was observed between BMI and total testosterone (B = -0.378, P < 0.001), sex hormone binding globulin (B = -0.572, P < 0.001), inhibin B (B = -3.120, P < 0.001) and anti-Müllerian hormone (AMH) (B = -0.009, P < 0.001). Our findings suggest that high BMI is negatively associated with semen characteristics and serum levels of AMH.


Stimulator of interferon genes is required for Toll-Like Receptor-8 induced interferon response.
The innate immune system is equipped with multiple receptors to detect microbial nucleic acids and induce type I interferon (IFN) to restrict viral replication. When dysregulated these receptor pathways induce inflammation in response to host nucleic acids and promote development and persistence of autoimmune diseases like Systemic Lupus Erythematosus (SLE). IFN production is regulated by the Interferon Regulatory Factor (IRF) transcription factor family of proteins that function downstream of several innate immune receptors such as Toll-like receptors (TLRs) and Stimulator of Interferon Genes (STING). Although both TLRs and STING activate the same downstream molecules, the pathway by which TLRs and STING activate IFN response are thought to be independent. Here we show that STING plays a previously undescribed role in human TLR8 signaling. Stimulation with the TLR8 ligands induced IFN secretion in primary human monocytes, and inhibition of STING reduced IFN secretion from primary monocytes from 8 healthy donors. We demonstrate that TLR8-induced IRF activity was reduced by STING inhibitors. Moreover, TLR8-induced IRF activity was blocked by inhibition or loss of IKKε, but not TBK1. Bulk RNA transcriptomic analysis supported a model where TLR8 induces transcriptional responses associated with SLE that can be downregulated by inhibition of STING. These data demonstrate that STING is required for full TLR8-to-IRF signaling and provide evidence for a new framework of crosstalk between cytosolic and endosomal innate immune receptors, which could be leveraged to treat IFN driven autoimmune diseases. High levels of type I interferon (IFN) is characteristic of multiple autoimmune diseases, and while TLR8 is associated with autoimmune disease and IFN production, the mechanisms of TLR8-induced IFN production are not fully understood. STING is phosphorylated following TLR8 signaling, which is selectively required for the IRF arm of TLR8 signaling and for TLR8-induced IFN production in primary human monocytes. STING plays a previously unappreciated role in TLR8-induced IFN production. Nucleic acid-sensing TLRs contribute to development and progression of autoimmune disease including interferonopathies, and we show a novel role for STING in TLR-induced IFN production that could be a therapeutic target.


Cytokine, chemokine alterations and immune cell infiltration in Radiation-induced lung injury: Implications for prevention and management.
Radiation therapy is one of the primary treatments for thoracic malignancies, with radiation-induced lung injury (RILI) emerging as its most prevalent complication. RILI encompasses early-stage radiation pneumonitis (RP) and the subsequent development of radiation pulmonary fibrosis (RPF). During radiation treatment, not only are tumor cells targeted, but normal tissue cells, including alveolar epithelial cells and vascular endothelial cells, also sustain damage. Within the lungs, ionizing radiation boosts the intracellular levels of reactive oxygen species across various cell types. This elevation precipitates the release of cytokines and chemokines, coupled with the infiltration of inflammatory cells, culminating in the onset of RP. This pulmonary inflammatory response can persist, spanning a duration from several months to years, ultimately progressing to RPF. This review aims to explore the alterations in cytokine and chemokine release and the influx of immune cells post-ionizing radiation exposure in the lungs, offering insights for the prevention and management of RILI.


A comparison of meta-analysis results with and without adjustment for the healthy worker effect: cancer mortality among workers in the semiconductor industry.
This study compared the results of meta-analysis with and without adjustment for the healthy worker effect on the association between working in the semiconductor industry and cancer mortality. Six studies that reported standardized mortality ratios (SMRs) for cancers were selected for meta-analysis. Using a random-effects model, the SMR results from each study were combined for all cancers and leukemias to estimate the summary SMRs (95% confidence interval, CI). To adjust for the healthy worker effect, the relative standardized mortality ratio (rSMR=SMRx/SMRnot x) were calculated using observed and expected counts for the specific cause of interest (i.e., all cancers and leukemias) and the observed and expected counts for all other causes of mortality. Then, the rSMR results were combined to estimate the summary rSMRs (95% CIs). The SMRs for all causes of mortality among semiconductor industry workers ranged from 0.25 to 0.80, which reflects a significant healthy worker effect. A remarkable difference was found between the summary SMRs and the summary rSMRs. The summary SMR for all cancers was 0.70 (95% CI, 0.63 to 0.79) whereas the summary rSMR was 1.38 (95% CI, 1.20 to 1.59). The summary SMR for leukemia was 0.88 (95% CI, 0.72 to 1.07), and the summary rSMR was 1.88 (95% CI, 1.20 to 2.95). Our results suggest that adjustment for the healthy worker effect (i.e., rSMR) may be useful in meta-analyses of cohort studies reporting SMRs.


Meeting report from the second EurocanPlatform summer school on translational cancer research, Portugal, 20-24 October 2014.
The second EurocanPlatform summer school was held in Algarve, Portugal and attracted scientists, clinicians and pathologists with a common interest in cancer research to discuss the latest developments and challenges in the field. The meeting focused on translational cancer research and also included lectures, workshops and discussions, which covered all aspects of the translational research continuum, from early detection through treatment to survivorship. The rate of new cancer cases and cancer mortality increases every year. Although the last decade witnessed enormous progress in understanding cancer biology and the development of new therapies, the efficacy of these therapies is challenged by cancer resistance. It clearly suggests that new druggable targets are required and their translation from laboratory to bedside must be faster and more efficient to improve survival rates and standards of care.


Microfluidic immunosensor design for the quantification of interleukin-6 in human serum samples.
Interleukin-6 (IL-6), an inflammatory cytokine, is one of the most important mediators of fever, the acute phase response, and inflammatory conditions. Described here is an integrated microfluidic immunosensor capable of detecting the concentration of IL-6 in human serum samples by use of an electrochemical method in a microfluidic biochip format. The detection of IL-6 was carried out using a sandwich immunoassay method based on the use of anti-IL-6 monoclonal antibodies, immobilized on a 3-aminopropyl-modified controlled-pore glass (APCPG) packet in a central channel (CC) of the microfluidic system. The IL-6 in the serum sample is allowed to react immunologically with the immobilized anti-IL-6 and biotin-labeled second antibodies specific to IL-6. After washing, the streptavidin-alkaline phosphatase conjugate is added. p-Aminophenyl phosphate is converted to p-aminophenol by alkaline phosphatase, and the electroactive product is quantified on a gold electrode at 0.10 V. For electrochemical detection and enzyme immunoassay, the LOD was 0.41 and 1.56 pg mL(-1), respectively. Reproducibility assays employed repetitive standards of IL-6, and the intra- and inter-assay coefficients of variation were below 6.5%. Compared with the traditional IL-6 sensing method, the integrated microfluidic immunosensor required smaller amounts of sample to perform faster detection.


iBitter-Fuse: A Novel Sequence-Based Bitter Peptide Predictor by Fusing Multi-View Features.
Accurate identification of bitter peptides is of great importance for better understanding their biochemical and biophysical properties. To date, machine learning-based methods have become effective approaches for providing a good avenue for identifying potential bitter peptides from large-scale protein datasets. Although few machine learning-based predictors have been developed for identifying the bitterness of peptides, their prediction performances could be improved. In this study, we developed a new predictor (named iBitter-Fuse) for achieving more accurate identification of bitter peptides. In the proposed iBitter-Fuse, we have integrated a variety of feature encoding schemes for providing sufficient information from different aspects, namely consisting of compositional information and physicochemical properties. To enhance the predictive performance, the customized genetic algorithm utilizing self-assessment-report (GA-SAR) was employed for identifying informative features followed by inputting optimal ones into a support vector machine (SVM)-based classifier for developing the final model (iBitter-Fuse). Benchmarking experiments based on both 10-fold cross-validation and independent tests indicated that the iBitter-Fuse was able to achieve more accurate performance as compared to state-of-the-art methods. To facilitate the high-throughput identification of bitter peptides, the iBitter-Fuse web server was established and made freely available online. It is anticipated that the iBitter-Fuse will be a useful tool for aiding the discovery and de novo design of bitter peptides.


Source characterisation of atmospheric platinum group element deposition into an ombrotrophic peat bog.
Platinum, palladium, rhodium, iridium and osmium were found to be enriched relative to their expected natural concentrations in peat samples from Thoreau's Bog, an ombrotrophic peat bog in Concord, Massachusetts. The source of osmium into the bog was determined from its isotopic composition (187Os/188Os). Osmium is composed of 4% lithogenic osmium from atmospheric soil dust, 41% of anthropogenic osmium and 55% of osmium from a non-lithogenic, non anthropogenic source, with rain being a likely candidate for the latter. Significant anthropogenic and rain contributions are also expected for iridium. In contrast, platinum, palladium and rhodium are almost exclusively anthropogenic. The larger enrichments of platinum, palladium and rhodium indicate that automobile catalysts are the source of platinum group elements to Thoreau's bog. The bog is located approximately 300 m from a major road and, therefore, the occurrence of platinum elements is evidence for regional dispersion of these metals. The absence of a clear trend following the introduction of catalysts indicates that platinum group elements are not quantitatively conserved in peat with downward leaching and plants playing an important role in the accumulation of platinum group elements.


Bifunctional folic-conjugated aspartic-modified Fe3O4 nanocarriers for efficient targeted anticancer drug delivery.
Functionalization of nanocarriers has been considered the most promising way of ensuring an accurate and targeted drug delivery system. This study reports the synthesis of bifunctional folic-conjugated aspartic-modified Fe3O4 nanocarriers with an excellent ability to deliver doxorubicin (DOX), an anticancer drug, into the intercellular matrix. Here, the presence of amine and carboxylate groups enables aspartic acid (AA) to be used as an efficient anchoring molecule for the conjugation of folic acid (FA) (EDC-NHS coupling) and DOX (electrostatic interaction). Based on the results, surface functionalization showed little effect on the physicochemical properties of the nanoparticles but significantly influenced both the loading and release efficiency of DOX. This is primarily caused by the steric hindrance effect due to large and bulky FA molecules. Furthermore, in vitro MTT assay of B16-F1 cell lines revealed that FA conjugation was responsible for a significant increase in the cytotoxicity of DOX-loaded nanocarriers, which was also found to be proportional to AA concentration. This high cytotoxicity resulted from an efficient cellular uptake induced by the over-expressed folate receptors and fast pH triggered DOX release inside the target cell. Here, the lowest IC50 value of DOX-loaded nanocarriers was achieved at 2.814 ± 0.449 μg mL-1. Besides, further investigation also showed that the drug-loaded nanocarriers exhibited less or no toxicity against normal cells.


[Population of murine rhabdomyosarcoma MKh-53 clones under different proliferation conditions studied by flow cytometry].
Clones of rhabdomyosarcoma cells were obtained due to implantation of the tumor cells in the eye anterior chamber, in subcutaneous connective tissue and in lungs of mice. The DNA contents in the clone cells were measured using flow cytometry. Diploid indices of clones were calculated from the ratio of the modal content of DNA in G1-cells to the DNA content in lymphocytes contaminating these clones. The diploid indices of various clones varied from 1.4 to 2.3. The mean diploid index calculated for clones that grew under given conditions of proliferation varied within 1.85-1.88. Only one of the 66 clones examined displayed a two-peak distribution of cell according to their DNA content in phase G1, which may suggest a karyotypic instability of the progeny of the tumor clonogenic cell. No correlation was revealed between the diploid indices of clones and the following parameters, such as: the portion of tumor cells being at different phases of cell cycle; the number of normal (stromal) cells contaminating the clones, coefficients of variation of DNA contents in tumor cell clones. A positive correlation was observed between the coefficients of variation of DNA contents in the normal (stromal) cells contaminating the clones and those of tumor clone cells being in phase G1. It is concluded that the variability of results of the flow cytometric measurement of DNA in G1-cells may reflect the variability of cells in respect not only to their DNA contents but also to their capacity of dye sorbtion.


Two medieval plague treatises and their afterlife in early modern England.
This study of an adaptation of the popular John of Burgundy plague treatise by Thomas Moulton, a Dominican friar, ca. 1475, and a translation of the so-called Canutus plague treatise by Thomas Paynell, printed 1534, shows how the medieval traditions they represent were carried forward, well into the sixteenth century, and also subjected to change in light of religious, moral, and medical concerns of early modern England. The former had a long life in print, ca. 1530-1580, whereas Paynell's translation exists in one printed version. Moulton's adaptation differs from its original and from the Canutus treatise in putting great emphasis on the idea that onsets of plague were acts of divine retribution for human sinfulness. In this respect, Moulton reshaped the tradition of the medieval plague treatise and anticipated the religious and social construction of plague that would take shape in the first half of the sixteenth century. Its long history in print indicates that Moulton's treatise expressed the spirit of that construction and probably influenced the construction as well. The contrasting histories of the two treatises attest not only to the dramatic change brought about by religious and social forces in the sixteenth century, but to a growing recognition of the value of the printing press for disseminating medical information-in forms that served social and ideological ends.


Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor.
Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRα and TCRβ chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the diverse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells.


Gli1+ Pericyte Loss Induces Capillary Rarefaction and Proximal Tubular Injury.
Peritubular capillary rarefaction is hypothesized to contribute to the increased risk of future CKD after AKI. Here, we directly tested the role of Gli1+ kidney pericytes in the maintenance of peritubular capillary health, and the consequences of pericyte loss during injury. Using bigenic Gli1-CreERt2; R26tdTomato reporter mice, we observed increased distance between Gli1+ pericytes and endothelial cells after AKI (mean±SEM: 3.3±0.1 µm before injury versus 12.5±0.2 µm after injury; P<0.001). Using a genetic ablation model, we asked whether pericyte loss alone is sufficient for capillary destabilization. Ten days after pericyte ablation, we observed endothelial cell damage by electron microscopy. Furthermore, pericyte loss led to significantly reduced capillary number at later time points (mean±SEM capillaries/high-power field: 67.6±4.7 in control versus 44.1±4.8 at 56 days; P<0.05) and increased cross-sectional area (mean±SEM: 21.9±0.4 µm2 in control versus 24.1±0.6 µm2 at 10 days; P<0.01 and 24.6±0.6 µm2 at 56 days; P<0.001). Pericyte ablation also led to hypoxic focal and subclinical tubular injury, reflected by transient expression of Kim1 and vimentin in scattered proximal tubule segments. This analysis provides direct evidence that AKI causes pericyte detachment from capillaries, and that pericyte loss is sufficient to trigger transient tubular injury and permanent peritubular capillary rarefaction.


Anti-Herpetic Activity of Callissia fragrans and Simmondsia chinensis Leaf Extracts In Vitro.
The antiviral activity of Callissia fragrans and Simnondsia chinensis aquatic and ethanol leaf extracts, as well as purified fractions from these extracts was studied against herpetic viruses in vitro. Ethanol extract of C. fragrans effectively inhibited the infection of Vero cells by HSV-1, HSV-2 in vitro, while its aquatic extract inhibited only VZV. Although S. chinensis leaf extract strongly inhibited all studied viruses, the selectivity index of this extract was very low, due to its high toxicity. However, the majority of its fractions showed low toxicity and higher antiviral activity and therefore very high SI. Strong interactions between virus and extracts were found.


Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology: A Review of Their Utilization, Safety Profile and Future Applications.
Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-inclass, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.


Visceral nociception: peripheral and central aspects of visceral nociceptive systems.
Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.


Circadian regulation of a-type potassium currents in the suprachiasmatic nucleus.
In mammals, the precise circadian timing of many biological processes depends on the generation of oscillations in neural activity of pacemaker cells in the suprachiasmatic nucleus (SCN) of the hypothalamus. Understanding the ionic mechanisms underlying these rhythms is an important goal of research in chronobiology. Previous work has shown that SCN neurons express A-type potassium currents (IAs), but little is known about the properties of this current in the SCN. We sought to characterize some of these properties, including the identities of IA channel subunits found in the SCN and the circadian regulation of IA itself. In this study, we were able to detect significant hybridization for Shal-related family members 1 and 2 (Kv4.1 and 4.2) within the SCN. In addition, we used Western blot to show that the Kv4.1 and 4.2 proteins are expressed in SCN tissue. We further show that the magnitude of the IA current exhibits a diurnal rhythm that peaks during the day in the dorsal region of the mouse SCN. This rhythm seems to be driven by a subset of SCN neurons with a larger peak current and a longer decay constant. Importantly, this rhythm in neurons in the dorsal SCN continues in constant darkness, providing an important demonstration of the circadian regulation of an intrinsic voltage-gated current in mammalian cells. We conclude that the anatomical expression, biophysical properties, and pharmacological profiles measured are all consistent with the SCN IA current being generated by Kv4 channels. Additionally, these data suggest a role for IA in the regulation of spontaneous action potential firing during the transitions between day/night and in the integration of synaptic inputs to SCN neurons throughout the daily cycle.


Sounds Like Respect. The Impact of Background Music on the Acceptance of Gay Men in Audio-Visual Advertising.
Companies increasingly seek to use gay protagonists in audio-visual commercials to attract a new affluent target group. There is also growing demand for the diversity present in society to be reflected in media formats such as advertising. Studies have shown, however, that heterosexual consumers (especially men), who may be part of the company's loyal consumer base, tend to react negatively to gay-themed advertising campaigns. Searching for an instrument to mitigate this unwanted effect, the present study investigated whether carefully selected background music can shape the perceived gender of gay male advertising protagonists. In a 2 × 2 between-subjects online experiment (musical connotation × gender of the participant), 218 heterosexual participants watched a commercial promoting engagement rings that featured gay male protagonists, scored with feminine- or masculine-connoted background music. As expected, women generally reacted more positively than men to the advertising. Men exposed to the masculine-connoted background music rated the promoted brand more positively, and masculine music also enhanced (at least in the short term) these men's acceptance of gay men in general (low and medium effect sizes) more than was the case for feminine background music. Carefully selected background music affecting the perceived gender of gay male advertising protagonists may prevent negative reactions from heterosexual audiences and, therefore, motivate companies to use gay protagonists in television commercials on a more regular basis.


High-mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter.
High-mobility group box 1 (HMGB1) was initially described as a damage-associated-molecular-pattern (DAMP) mediator that worsens acute brain injury after stroke. But, recent findings suggest that HMGB1 can play a surprisingly beneficial role during stroke recovery by promoting endothelial progenitor cell (EPC) function and vascular remodeling in cortical gray matter. Here, we ask whether HMGB1 may also influence EPC responses in white matter injury. The standard lysophosphatidylcholine (LPC) injection model was used to induce focal demyelination in the corpus callosum of mice. Immunostaining showed that within the focal white matter lesions, HMGB1 was up-regulated in GFAP-positive reactive astrocytes, along with the accumulation of Flk1/CD34-double-positive EPCs that expressed pro-recovery mediators such as brain-derived neurotrophic factor and basic fibroblast growth factor. Astrocyte-EPC signaling required the HMGB1 receptor RAGE as treatment with RAGE-neutralizing antibody significantly decreased EPC accumulation. Moreover, suppression of HMGB1 with siRNA in vivo significantly decreased EPC numbers in damaged white matter as well as proliferated endothelial cell numbers. Finally, in vitro cell culture systems confirmed that HMGB1 directly affected EPC function such as migration and tube formation. Taken together, our findings suggest that HMGB1 from reactive astrocytes may attract EPCs to promote recovery after white matter injury.


Attitudes and perceptions of medical students about family medicine in Spain: protocol for a cross-sectional survey.
Background Despite the fact that family medicine (FM) has become established as a specialty in the past 25 years, this has not been reflected in the inclusion of the specialty in the majority of medical schools in Spain. Almost 40% of the students will work in primary care but, in spite of this, most universities do not have an assessed placement as such. There are only specific practice periods in health centres or some student-selected components with little weight in the overall curricula. Objectives To evaluate the attitudes and perceptions of medical students about FM in the health system and their perception about the need for specific training in FM at the undergraduate level. To explore change over time of these attitudes and perceptions and to examine potential predictive factors for change. Finally, we will review what teaching activity in FM is offered across the Spanish schools of medicine. Methods Descriptive cross-sectional survey. Each one of the different analyses will consist of two surveys: one for all the students in the first, third and fifth year of medical school in all the Spanish schools of medicine asking about their knowledge, perceptions and attitudes in relation to primary care and FM. There will be an additional survey for the coordinating faculty of the study in each university about the educational activities related to FM that are carried out in their centres. The repetition of the study every 2 years will allow for an analysis of the evolution of the cohort of students until they receive their degree and the potential predictive factors. Discussion This study will provide useful information for strategic planning decisions, content and educational methodology in medical schools in Spain and elsewhere. It will also help to evaluate the influence of the ongoing changes in FM, locally and at the European level, on the attitudes and perceptions of the students towards FM in Spain.


The Implementation of Early Detection in Tuberculosis Contact Investigation to Improve Case Finding.
The early detection of Tuberculosis (TB) among TB contacts is a strategy to find TB cases in earlier stage and to stop the transmission. This study aimed to assess the implementation of early detection in TB contact investigation to improve TB case finding. This was an operational research study conducted in Badung District, Bali, Indonesia. The samples were TB contacts, identified in the period July through September (third quarter) 2017. Contacts were household members who were living and sharing a room at least for 3 months with infectious TB patients and were not previously diagnosed with TB. Data were collected through face-to-face interview using structured questionnaires and registration reviews using a checklist. We visited 124 TB patients and successfully identified 498 contacts, thus the ratio of contacts to cases is 4:1. All TB contacts were invited to participate in TB screening and evaluation program. A total of 100 (20.1%) contacts have attended at least one examination session and 41 contacts have completed all sessions. Ten TB cases were found among the contacts, of which four of them were adults (three bacteriologically confirmed and one clinically confirmed) and six were children (aged under 15 years). The positivity rate among children was higher (46.2%) compared with adults (14.3%). The positivity rate of confirmed TB among contacts with any TB symptoms was 43.8% and that without symptoms was 12.0%. The contribution of early detection in TB contact investigation to improve TB case finding was 8.1% through all TB patients. The early detection in TB contact investigation yielded additional notified cases, especially among children. A comprehensive education, covering cognitive and psychological aspect, is needed to encourage TB contacts to completely participate in early detection program until their diagnosis is confirmed.


Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis.
Kainate-induced seizures increase hippocampal neurogenesis. Glial fibrillary acidic protein-positive astrocytes with radial processes in the dentate gyrus share many of the characteristics of radial glia and appear to act as precursor cells for adult dentate neurogenesis. Using the chemoconvulsant kainate and transgenic mice with human glial-fibrillary acidic protein (hGFAP) promoter-controlled enhanced green fluorescent protein (EGFP) expression, we examined the proliferation, morphology and electrophysiological properties of astrocytes in the neurogenic subgranular zone of the dentate gyrus in control animals and upon the induction of seizure-induced cell proliferation, three days post-kainate. EGFP-positive cells with and without radial processes could easily be distinguished. Kainate treatment caused a significant increase in the total number of proliferating EGFP-positive cells, particularly a tenfold elevation in the number of proliferating radial glia-like astrocytes, and also caused a preferential shift in the dividing cell population towards cells expressing EGFP. Immunohistochemical analysis revealed a surprisingly low proportion of cells coexpressing the astroglial marker S100beta and EGFP. Kainate increased the number of EGFP-positive, S100beta-positive and S100beta-positive-EGFP-positive astrocytes in the subgranular zone. We also report a subset of faintly EGFP-positive cells expressing markers of early neuronal differentiation. Patch-clamp analysis revealed the presence of three functionally different populations of EGFP-positive cells in both kainate and control tissue. We conclude that there is an early increase in proliferating radial glia-like astrocytes in the dentate after kainate-induced seizures, consistent with a recruitment of precursors for seizure-induced neurogenesis.


Development and Examination of a Family Triadic Measure to Examine Quality of Life Family Congruence in Nursing Home Residents and Two Family Members.
Objective: The overall purpose of this study was to propose and test a conceptual model and apply family analyses methods to understand quality of life family congruence in the nursing home setting. Method: Secondary data for this study were from a larger study, titled Measurement, Indicators and Improvement of the Quality of Life (QOL) in Nursing Homes. Research literature, family systems theory and human ecological assumptions, fostered the conceptual model empirically testing quality of life family congruence. Results: The study results supported a model examining nursing home residents and two family members on quality of life family congruence. Specifically, family intergenerational dynamic factors, resident personal and social-psychological factors, and nursing home family input factors were examined to identify differences in quality of life family congruence among triad families. Discussion: Formal family involvement and resident cognitive functioning were found as the two most influential factors to quality of life family congruence (QOLFC).


Saturation of an intra-gene pool linkage map: towards a unified consensus linkage map for fine mapping and synteny analysis in common bean.
Map-based cloning and fine mapping to find genes of interest and marker assisted selection (MAS) requires good genetic maps with reproducible markers. In this study, we saturated the linkage map of the intra-gene pool population of common bean DOR364 × BAT477 (DB) by evaluating 2,706 molecular markers including SSR, SNP, and gene-based markers. On average the polymorphism rate was 7.7% due to the narrow genetic base between the parents. The DB linkage map consisted of 291 markers with a total map length of 1,788 cM. A consensus map was built using the core mapping populations derived from inter-gene pool crosses: DOR364 × G19833 (DG) and BAT93 × JALO EEP558 (BJ). The consensus map consisted of a total of 1,010 markers mapped, with a total map length of 2,041 cM across 11 linkage groups. On average, each linkage group on the consensus map contained 91 markers of which 83% were single copy markers. Finally, a synteny analysis was carried out using our highly saturated consensus maps compared with the soybean pseudo-chromosome assembly. A total of 772 marker sequences were compared with the soybean genome. A total of 44 syntenic blocks were identified. The linkage group Pv6 presented the most diverse pattern of synteny with seven syntenic blocks, and Pv9 showed the most consistent relations with soybean with just two syntenic blocks. Additionally, a co-linear analysis using common bean transcript map information against soybean coding sequences (CDS) revealed the relationship with 787 soybean genes. The common bean consensus map has allowed us to map a larger number of markers, to obtain a more complete coverage of the common bean genome. Our results, combined with synteny relationships provide tools to increase marker density in selected genomic regions to identify closely linked polymorphic markers for indirect selection, fine mapping or for positional cloning.


Systemic immune activation as a potential determinant of wasting in Zambians with HIV-related diarrhoea.
Wasting in African AIDS patients is severe, and its aetiology is probably multifactorial: persistent diarrhoea, poverty and tuberculosis may all contribute. We report a cross-sectional study of body composition measured anthropometrically in 75 adult patients with HIV-related persistent diarrhoea in Lusaka, and its relationship to gastrointestinal infection and systemic immune activation assessed using serum neopterin and soluble tumour necrosis factor receptor (sTNF-R55) concentrations. Patients as a group were generally severely wasted (mean body mass index (BMI) 15.8 kg/m2, range 11-22), but the severity of wasting was related neither to oesophageal candidiasis nor to intestinal infection. In men but not women, all measures of nutritional status were negatively related to serum sTNF-R55 concentration (fat-free mass in men, r = -0.64; 95% CI: -0.80, -0.41; p < 0.0001). Some wasted patients had cutaneous features of malnutrition, again associated with higher sTNF55 concentrations, and two had peripheral oedema. The diarrhoea-wasting syndrome in this part of Africa seems to be associated with evidence of high cytokine activity in men, rather than oesophageal candidiasis or any particular intestinal opportunistic infection. This immune activation requires further investigation in the context of the sex difference we have observed.


Cyto-colpo-histologic correlation: about an analytical study of 120 colposcopies.
Cervical cancer is the second gynecological cancer Tunisian women after breast. This is a sexually transmitted disease including the role of HPV has been proven. Cervical cancer screening is possible due to the accessibility of the cervix with a speculum examination and implementation of cervical smear. To study the epidemiological and clinical data of patients, analyze the results of the Pap test, colposcopy and cervical biopsy staging are the lesions observed in colposcopy, compare the results of smears, colposcopy and cervical biopsy. A retrospective analytical study about 120 observations of patients who underwent colposcopy and biopsy of the cervix over a seven year period from January 2006 to December 2012. The mean age of patients was 46.6 years. The mean gravidity was 4.99. The mean parity was 4.07. The average age of first sexual intercourse was 24 years. 95.83% of the patients were married. Four patients had multiple partners, 3, 33%. Eighty-one patients 67.5% were genital activity. Two patients had a history of pelvic infection is 1.66%. A history of repeated low genital infection were found in 20 patients, or 16.66%. HPV testing was requested for two patients. The genotypes found were 16, 35 and 53. The most common reasons were essentially pathological smears, pelvic pain and exploration of bleeding. The FCU was performed in 98 patients either in 81.66% of cases. The smear was pathological in 83 patients or 84.69% of smears. He showed: a persistent inflammatory smears in 64 women, or 65.30% of the cases, 6 ASCUS or 6.12% of cases, 13 cervical dysplasia or 13.26% of cases: 8 CIN1 or 8.16% of event; 1 CIN2 or 1.02% and 4 CIN 3, or 4.08% of cases. Colposcopy was indicated before an abnormal smear: In 83 patients either in 69.16% of cases. Colposcopy was performed in front of an abnormal appearance of the cervix in 37 patients. Colposcopy has concluded that: normal cervix in 28 patients or 23.33% of the cases, cervicitis appearance in 15 patients or 12.5% of cases, ectropion in 23 patients or 19.2% of cases, with TAGI 47 patients or 39.2% of cases, a TAG2 in 6 patients either 5% of cases, ulceration in a patient or 0.83% of cases. Cervical biopsy objectified normal mucosa in 19 patients, or 15.8% of cases. She objectified cervical metaplasia in 11 patients, or 9.2% of cases, ectropion in a patient, or 0.8% of cases, cervicitis in 56 patients, or 46.7% of cases, condyloma in 2 patients, 1.7% of cases, CIN 1 in 6 patients, 5% of cases, CIN2 in 4 patients, soit3,3% of CIN3 and in 3 patients, 2.5% of cases. FCU had a sensitivity of 60%, a specificity of 95.18%, positive predictive value of 69% and a negative predictive value of 93%. The sensitivity of colposcopy was 66% and specificity of59%. Positive predictive value of 18% and a negative predictive value of 92%. For high-grade dysplasia, colposcopy had a sensitivity of 85%, specificity 58%, positive predictive value of 11.3% and a negative predictive value of 98%. Cervical biopsy finds carcinoma in situ in two cases and squamous micro-invasive carcinoma in one case. The treatments were performed essentially a cervical electrocoagulation in 8 patients, a cone biopsy in 7 patients and post conization hysterectomy in 2 patients. Colposcopy is a harmless and reliable examination to guide the cervical biopsy. Tracks smear, colposcopy and directed biopsy confirmed.


Enrichment, isolation, and cultural characteristics of marine strains of Clostridium botulinum type C.
Terrestrial strains of Clostridium botulinum type C, designated 468 and 571, were used to screen various media for growth and sporulation at 30 C. Of the various formulations tested, only egg meat medium fortified with 1% additions of yeast extract, ammonium sulfate, and glucose (FEM medium) gave good growth and satisfactory sporulation. FEM medium was used to recover four marine type C isolates from inshore sediments collected along the Atlantic, the Gulf of Mexico, and the Pacific coasts of the United States. The isolation techniques involved repeated transfer of cultures showing type C toxin in FEM medium and purification by a deep tube method. The medium used for purification was beef infusion-agar supplemented with 0.14% sodium bicarbonate and 0.1% l-cysteine hydrochloride. l-Cysteine was adopted in preference to sodium thioglycolate, because some lots of the latter were definitely inhibitory for growth. The addition of bicarbonate markedly increased viable spore counts of both the marine and terrestrial strains. Various cultural and biochemical characteristics of the marine and the terrestrial strains were compared. With the exception of some variations in their fermentation patterns, both groups showed similar characteristics. Of 23 fermentable compounds tested, the terrestrial strains attacked only glucose and mannose. The marine strains fermented glucose, mannose, galactose, and ribose actively; dextrin, inositol, maltose, and melibiose were weakly fermented.


Dietary Polyphenol and Methylsulfonylmethane Supplementation Improves Immune, DAMP Signaling, and Inflammatory Responses During Recovery From All-Out Running Efforts.
Nutritional ingredients with defined mechanisms of action can be useful in the recovery of the body from the physical demands of a habitual training plan. The purpose of this study was to determine the effect of dietary supplementation with optimized curcumin, pomegranate ellagitannins, and MSM (R + MSM) on immune-associated mRNA during early recovery (i.e., up to 8 h post-exercise) following all-out running efforts (5-km, 10-km, and 21.1-km). Subjects (N = 14) were randomized to either a supplement (R + MSM) or a control group using an open label design. The study was completed over a period of 31-day prior to a scheduled half-marathon race. Venous blood samples were collected into PAXgene tubes at baseline, subsequent samples were collected at 2, 4, and 8 h after each running effort. A 574-plex mRNA Immunology Array (NanoString) was measured for each sample and ROSALIND® Advanced Analysis Software was used to examined changes in 31 annotated immune response pathways and specific mRNA changes. The greatest change in immune pathways occurred at 2 h (GSS > 3) followed by 4 h (GSS 2-3) and 8 h (GSS 1-2). R + MSM was associated with an increase in innate immunity (CAMP, LTF, TIRAP, CR1, IL1R1, CXCR1, PDCDILG2, and GNLY) and a blunted/smaller increase in damage-associated molecular pattern (DAMP) signaling/inflammation (TLR4, TLR5, S100A8, S100A9, and IFP35). We also found changes in immune-associated mRNA that have not been previously linked to exercise recovery (SOCS1, SOCS2, MME, CECAM6, MX1, IL-1R2, KLRD1, KLRK1, and LAMP3). Collectively these results demonstrate that supplementation with a combination of optimized curcumin, pomegranate ellagitannins, and methylsulfonylmethane resulted in changes that may improve biological recovery from all-out running efforts.


Multifunctional T-cell characteristics induced by a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 vaccine regimen given to healthy adults are dependent on the route and dose of administration.
A phase I clinical vaccine study of a human immunodeficiency virus type 1 (HIV-1) vaccine regimen comprising a DNA prime formulation (5-valent env and monovalent gag) followed by a 5-valent Env protein boost for seronegative adults was previously shown to induce HIV-1-specific T cells and anti-Env antibodies capable of neutralizing cross-clade viral isolates. In light of these initial findings, we sought to more fully characterize the HIV-1-specific T cells by using polychromatic flow cytometry. Three groups of participants were vaccinated three times with 1.2 mg of DNA administered intradermally (i.d.; group A), 1.2 mg of DNA administered intramuscularly (i.m.; group B), or 7.2 mg of DNA administered i.m. (high-dose group C) each time. Each group subsequently received one or two doses of 0.375 mg each of the gp120 protein boost vaccine (i.m.). Env-specific CD4 T-cell responses were seen in the majority of participants; however, the kinetics of responses differed depending on the route of DNA administration. The high i.m. dose induced the responses of the greatest magnitude after the DNA vaccinations, while the i.d. group exhibited the responses of the least magnitude. Nevertheless, after the second protein boost, the magnitude of CD4 T-cell responses in the i.d. group was indistinguishable from those in the other two groups. After the DNA vaccinations and the first protein boost, a greater number of polyfunctional Env-specific CD4 T cells (those with > or = 2 functions) were seen in the high-dose group than in the other groups. Gag-specific CD4 T cells and Env-specific CD8 T cells were seen only in the high-dose group. These findings demonstrate that the route and dose of DNA vaccines significantly impact the quality of immune responses, yielding important information for future vaccine design.


[Biological correlates of prefrontal activating and temporoparietal inhibiting treatment with repetitive transcranial magnetic stimulation (rTMS)].
Repetitive transcranial magnetic stimulation (rTMS) is a tool that enables clinicians and neuroscientists to modulate cortical activity in a non-invasive way. High-frequency rTMS has predominantly an activating effect on the stimulated brain region while low-frequency rTMS has an inhibitory effect. In addition to its usefulness as a research tool and in neurological diagnostics, rTMS may prove useful as a therapeutic option in psychiatry, especially in disorders that are associated with regional changes in cortical activity. For instance, rTMS is under current investigation in the treatment of depression and negative symptoms of schizophrenia. A hypofrontality or a fronto-limbic imbalance associated with both syndromes could be corrected by activating, high frequency rTMS. Conversely, a regional hyperactivity in the temporo-parietal cortex has been described in subjects suffering from auditory hallucinations and tinnitus. Low frequency, inhibitory rTMS is currently evaluated as a therapeutic option in these subjects. In addition to the effects on the directly stimulated brain area, other biological effects of rTMS may exert a beneficial influence on brain function. Amongst these are a modulation of cortico-cortical circuits (e. g. fronto-cingular and fronto-parietotemporal circuits), effects on monoaminergic neuromodulation and neuroendocrine effects. The current knowledge about the therapeutically relevant neurophysiological and neuroendocrine effects of rTMS are reviewed. An improved understanding of the neurophysiological basis of the therapeutic effects of rTMS and of the pathophysiology underlying neuropsychiatric diseases may lead to optimized therapeutic rTMS applications and new clinical indications for rTMS.


Structure, stoichiometry and transport properties of lithium copper nitride battery materials: combined NMR and powder neutron diffraction studies.
A combined NMR and neutron diffraction study has been carried out on three Li(3-x-y)Cu(x)N materials with x=0.17, x=0.29 and x=0.36. Neutron diffraction indicates that the samples retain the P6/mmm space group of the parent Li(3)N with Cu located only on Li(1) sites. The lattice parameters vary smoothly with x in a similar fashion to Li(3-x-y)Ni(x)N, but the Li(2) vacancy concentration for the Cu-substituted materials is negligible. This structural model is confirmed by wideline (7)Li NMR spectra at 193 K which show three different local environments for the Li(1) site, resulting from the substitution of neighbouring Li atoms in the Li(1) layer by Cu. Since the Cu-substituted materials are only very weakly paramagnetic, variable temperature (7)Li wideline NMR spectra can be used to measure diffusion coefficients and activation energies. These indicate anisotropic Li(+) diffusion similar to the parent Li(3)N with transport confined to the [Li(2)N] plane at low temperature and exchange between Li(1) and Li(2) sites dominant at high temperature. For the intra-layer process the diffusion coefficients at room temperature are comparable to Li(3)N and Li(3-x-y) Ni(x)N, while E(a) decreases as x increases in contrast to the opposite trend in Ni-substituted materials. For the inter-layer process E(a) decreases only slightly as x increases, but the diffusion coefficients at room temperature increase rapidly with x.


Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.
Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. These findings support the administration of hormone therapy that mimics physiology.


Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA.
Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential.


Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement.
HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches.


Drift reduction in an optical heterodyne fiber gyro.
An optical heterodyne fiber gyro, which we recently proposed, is improved to reduce the zero-point drift. A reference interferometer is introduced in the improved configuration beside the sensing interferometer to obtain the Sagnac phase shift, which monitors the drift caused in the optical system. Experimental results demonstrate successful reduction of the drift.


Refractory versus resistant hypertension: Novel distinctive phenotypes.
Resistant hypertension (RHTN) is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is defined as blood pressure (BP) >140/90 mmHg treated with ≥3 antihypertensive medications, including a diuretic, if tolerated. Refractory hypertension is a novel phenotype of severe antihypertensive treatment failure. The proposed definition for refractory hypertension, i.e. BP >140/90 mmHg with use of ≥5 different antihypertensive medications, including a diuretic and a mineralocorticoid receptor antagonist (MRA) has been applied inconsistently. In comparison to RHTN, refractory hypertension seems to be less prevalent than RHTN. This review focuses on current knowledge about this novel phenotype compared with RHTN including definition, prevalence, mechanisms, characteristics and comorbidities, including cardiovascular risk. In patients with RHTN excess fluid retention is thought to be a common mechanism for the development of RHTN. Recently, evidence has emerged suggesting that refractory hypertension may be more of neurogenic etiology due to increased sympathetic activity as opposed to excess fluid retention. Treatment recommendations for RHTN are generally based on use and intensification of diuretic therapy, especially with the combination of a long-acting thiazide-like diuretic and an MRA. Based on findings from available studies, such an approach does not seem to be a successful strategy to control BP in patients with refractory hypertension and effective sympathetic inhibition in such patients, either with medications and/or device based approaches may be needed.


Fibre-optic sensors in health care.
Biomedical fibre-optic sensors are attractive for the measurement of physical, chemical and biochemical parameters and for spectral measurements directly performed on the patient. An overview of fibre-optic sensors for in vivo monitoring is given, with particular attention paid to the advantages that these sensors are able to offer in different application fields such as cardiovascular and intensive care, angiology, gastroenterology, ophthalmology, oncology, neurology, dermatology and dentistry.


Using task effort and pupil size to track covert shifts of visual attention independently of a pupillary light reflex.
We tested the link between pupil size and the task effort involved in covert shifts of visual attention. The goal of this study was to establish pupil size as a marker of attentional shifting in the absence of luminance manipulations. In three experiments, participants evaluated two stimuli that were presented peripherally, appearing equidistant from and on opposite sides of eye fixation. The angle between eye fixation and the peripherally presented target stimuli varied from 12.5° to 42.5°. The evaluation of more distant stimuli led to poorer performance than did the evaluation of more proximal stimuli throughout our study, confirming that the former required more effort than the latter. In addition, in Experiment 1 we found that pupil size increased with increasing angle and that this effect could not be reduced to the operation of low-level visual processes in the task. In Experiment 2 the pupil dilated more strongly overall when participants evaluated the target stimuli, which required shifts of attention, than when they merely reported on the target's presence versus absence. Both conditions yielded larger pupils for more distant than for more proximal stimuli, however. In Experiment 3, we manipulated task difficulty more directly, by changing the contrast at which the target stimuli were presented. We replicated the results from Experiment 1 only with the high-contrast stimuli. With stimuli of low contrast, ceiling effects in pupil size were observed. Our data show that the link between task effort and pupil size can be used to track the degree to which an observer covertly shifts attention to or detects stimuli in peripheral vision.


Multiple roles of TorD-like chaperones in the biogenesis of molybdoenzymes.
Biogenesis of prokaryote molybdoenzymes is a complex process leading to the insertion of the molybdenum cofactor in the cytoplasm into a folded apoenzyme before transport through the cell membrane. Usually, specific chaperones belonging to the TorD family are required for the maturation of the molybdoenzymes of the dimethyl sulfoxide reductase family. These chaperones play a crucial role during the biogenesis and the incorporation of the molybdenum cofactor by interacting with the core of the apoprotein. Moreover, they are also involved in the protection of the apoproteins by binding to their N-terminal extremity in an early stage of synthesis. Finally, the TorD-like proteins may possess a proofreading activity and they could target their partners to the twin arginine translocation machinery system for cross-membrane transport of prefolded proteins. The roles of these chaperones during the different steps of molybdoenzyme biogenesis are described.


Distinguishing lone from group actor terrorists: A comparison of attitudes, ideologies, motivations, and risks.
The increasing recognition of the risks posed by lone-actor terrorists provides the impetus for understanding the psychosocial and ideological characteristics that distinguish lone from group actors. This study examines differences between lone and group actor terrorists in two domains: (i) attitudes toward terrorism, ideology, and motivation for terrorist acts; and (ii) empirically derived risk factors for terrorism. Using a cross-sectional research design and primary source data from 160 men convicted of terrorism in Iraq, this study applied bivariate and logistic regression analyses to assess group differences. It tested the hypothesis that there are no statistically significant differences between the groups. Bivariate analyses revealed that lone actors were less likely than group actors, to be unemployed, to cite personal or group benefit as the main motives for terrorist activity, and to believe that acts of terrorism achieved their goals. Regression analysis indicated that having an authoritarian father was the only factor that significantly predicted group membership, with group actors three times more likely to report this trait. Lone actors and group actors are almost indistinguishable except for certain differences in attitudes, motives, employment, and having an authoritarian father.


Multimodality breast cancer screening in women with a familial or genetic predisposition.
Women with a predisposition for breast cancer require a tailored screening program for early cancer detection. We evaluated the performance of mammography (MG), ultrasonography (US), and magnetic resonance imaging (MRI) screening in these women. In asymptomatic women either confirmed as BRCA1/2 carriers, or having a greater than 30% probability of being so as estimated by brcapro [Berry D, Parmigiani G. Duke SPORE (Specialized Program of Research Excellence) in Breast Cancer. 1999], we conducted a prospective comparative trial consisting of annual MRI and MG, and biannual US and clinical breast examination. All evaluations were done within 30 days of one another. For each screening round, imaging tests were independently interpreted by three radiologists. The study enrolled 184 women, and 387 screening rounds were performed, detecting 12 cancers (9 infiltrating, 3 in situ), for an overall cancer yield of 6.5%. At diagnosis, 7 infiltrating cancers were smaller than 2 cm (T1); only 1 woman presented with axillary nodal metastases. All tumours were negative for the human epidermal growth factor receptor 2. Of the 12 cancers, MRI detected 10, and MG, 7; US did not identify any additional cancers. The overall recall rate after MRI was 21.8%, as compared with 11.4% for US and 16.1% for MG. Recall rates declined with successive screening rounds. In total, 45 biopsies were performed: 21 as a result of an US abnormality; 17, because of an MRI lesion; and 7, because of a MG anomaly. In high-risk women, MRI offers the best sensitivity for breast cancer screening. The combination of yearly MRI and MG reached a negative predictive value of 100%. The recall rate is greatest with MRI, but declines for all modalities with successive screening rounds.


Is the non-metastatic, locally advanced colon adenocarinoma a distinct biological tumor variant? A study based on pathological evaluation, immunohistochemical panel and survival.
to evaluate the clinical and pathological differences between locally advanced colonic adenocarcinomas (LACA) with adhesions between adjacent organs or structures, and colonic adenocarcinomas with other clinical presentations. we conducted a retrospective study from a convenience sample of patients with colonic adenocarcinoma, pathological stage pT3, distributed according to clinical and pathological characteristics in three groups: locally advanced tumors (LACA), pT3 tumors without adhesions or distant metastases (SF) and tumors with metastatic disease (M1). We evaluated clinical and pathological characteristics and the expression of seven immunohistochemical markers related to proliferation/apoptosis, cell invasion/migration and metastasis. we studied 101 patients: 30 LACA, 44 SF and 27 M1. Locally advanced tumors presented larger dimensions and were associated with increased lymphocyte infiltration rates, lower levels of bax expression, and CD 44v6 when compared with SF and M1 groups. We observed significant differences between LACA and M1 in relation to colonic location, histology, lymph node status and bax and CD44v6 expression. We found differences were observed between the three groups for tumor size and lymphocytic infiltrate. Survival was similar in the LACA and SF groups (p=0.66) and was lower in the M1 group (p<0.001). the data suggest that locally advanced colonic adenocarcinomas with adhesions between adjacent organs or structures represent a distinct entity.


Use of hematopoietic growth factors for in vitro expansion of precursor cell populations.
The increasing availability of recombinant human hematopoietic growth factors for clinical use has encouraged the development of novel approaches to the manipulation of hematopoiesis. Of particular note are the various strategies that have been proposed for ex vivo expansion of primitive hematopoietic cells. The majority of these involve growth of hematopoietic cells enriched in primitive progenitors in stromal cell-free suspension culture systems supported by the addition of various combinations of hematopoietic growth factors. In this article, we review recent progress in this area together with potential clinical applications for this technology.


Actin filament translocations in sea urchin eggs.
Rhodamine (rh) phalloidin was used as a probe for actin filaments in living eggs and was observed using confocal microscopy. Exogenous, rh phalloidin labeled actin filaments were injected into eggs and were observed to translocate in the cytoplasm. At fertilization, filaments accumulated at the fertilization cone. Rh phalloidin alone, injected at concentrations that did not interfere with fertilization or mitosis, labeled filaments in the interior of unfertilized eggs, some of which translocated. At fertilization, staining increased dramatically at the fertilization cone and to a lesser degree around the entire cortex. At about 9 min, many filaments appeared to detach and translocated away from the egg surface. This study shows that there are mechanisms that can translocate actin filaments within the egg cytoplasm (at approximately 0.2-0.3 mu m/sec), and raises the possibility that at least some of the changes in actin filament organization after fertilization are due to translocation of filaments.