Significance of the epidermal growth factor receptor mutation status and differences among molecular subgroups in surgically resected lung microinvasive adenocarcinoma.
Lung microinvasive adenocarcinoma (MIA) is a newly-defined subtype of early stage non-small cell lung cancer (NSCLC). However, its epidermal growth factor receptor (EGFR) mutation status and clinical significance remain unclear. The present study aimed to determine EGFR mutation characteristics and identify their significance in patients with resected lung MIA. The present study also analyzed clinicopathological differences between EGFR molecular subgroups defined as 19Del and L858R. The present study examined EGFR mutations in 79 consecutive lung MIA resection specimens and compared the differences in clinicopathological features between the EGFR wild-type and mutation groups, as well as between the 19Del and L858R subgroups. EGFR mutations were detected in 60 (75.95%) tumors. The most common mutations were 19Del (28 cases; 35.44%) and L858R (30 cases; 37.97%). Two patients harbored rare mutations and one of them had a concomitant double mutation. EGFR mutations were significantly associated with microinvasion component, thyroid transcription factor 1 (TTF-1) expression, intratumoral fibrosis and inflammatory cell infiltration. Subgroup evaluation indicated that there was a significant association between 19Del and tumor size, maximum diameter of microinvasion, presence of intratumoral fibrosis and inflammatory cell infiltration. Similar associations were observed for the L858R subgroup, and L858R was associated with TTF-1 expression. In particular, 19Del occurred more frequently in MIA with a smaller size, with a smaller microinvasive area, without TTF-1 expression, and lacking intratumoral fibrosis and inflammatory cell infiltration. By contrast, L858R was detected more frequently in MIA with entirely different tumor features. In conclusion, the results of the present study indicated that surgically resected MIA cases harboring different EGFR gene statuses exhibit distinct clinicopathological features. Significant differences in pathological features associated with the tumor microenvironment were identified in MIA with 19Del or L858R mutations. Therefore, the present study proposed that MIA should be classified into molecular subgroups based on EGFR mutation subtypes. The molecular sub-classification should be taken into account for prognostic evaluation and clinical management of MIA.


High-dose or low-dose cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer.
No randomized studies have compared low-dose or high-dose concurrent chemoradiotherapy (CRT). In this study, 7219 patients with stage III or IV head and neck squamous cell carcinoma (HNSCC) were enrolled and categorized into 2 groups: group 1, comprising those undergoing low-dose concurrent CRT (n = 1575), and group 2, comprising those receiving high-dose concurrent CRT (n = 5644). Cox regression analyses revealed that age ≥65 years, male, high Charlson comorbidity index (CCI) scores, radiotherapy (RT) duration ≥7.5 weeks, clinical stage IV cancer, oral cavity cancers, tobacco smoking, and total cisplatin dose ≥240 mg/m2 were significant independent prognostic risk factors for overall survival (OS). After adjustment for confounders, the adjusted hazard ratio (aHR; 95% confidence interval [CI]) for overall mortality was 0.83 (0.78-0.89; P < .001) in patients with oral cavity HNSCC undergoing high-dose concurrent CRT and 0.82 (0.77-0.94; P < .001) in patients with nonoral cavity HNSCC receiving high-dose concurrent CRT. High-dose concurrent CRT can reduce the incidence of death in patients with stage III or IV HNSCC.


Clueless: An ethnographic study of young men who participate in the seduction community with a focus on their psychosocial well-being and mental health.
In the last decade, a cross-national community of like-minded young men has emerged, commonly known as 'the seduction community'. This community is led by professional 'pick-up artists' who teach these young men a variety of techniques and mindsets with the stated aim of improving their success with women, or 'game'. There has been little research on the men who participate in this community, and none from a mental health angle. As such, this study is propelled by two specific objectives, namely documenting and understanding (i) the reasons why young men join the seduction community; and (ii) the impacts of community involvement on participants' lives. To meet these aims, we used an inductive qualitative methodology giving ample scope for bottom-up understandings to emerge. Specifically, we recruited young men participating in the seduction community for an in-depth qualitative interview (N = 34) to explore self-reported motives and impacts. Interviews were augmented by lengthy participant observation, and data was analyzed by content analysis techniques. The results reveal that men often join the community to address a range of psychosocial deficits, and that community involvement successfully equips participants with numerous valued social and communication skills. The community appears to fill a void in providing a place of hope, fellowship and learning for young (often immigrant) men. The findings are summarized in five themes (i) loneliness and social inclusion; (ii) lack of male role models and need for guidance; (iii) mental health and well-being issues; (iv) skill acquisition and personal development; and (v) the dark side of pick-up. Interestingly, some of the practices commonly taught and utilized within the community resemble aspects of Cognitive Behavioral Therapy and mental health peer support. This may explain its evident appeal. We conclude by reflecting on the implications of the findings for official mental health service provision for young men.


Population genetic studies of PI, Tf, Gc and PGM1 subtypes among various caste groups in North India.
Approximately 500 blood samples from various endogamous groups in north India have been subjected to isoelectric focusing to reveal genetic variation at the PI, Tf, Gc and PGM1 loci. The average heterozygosity per locus varies from 40% to 60% and the gene frequency data reflects considerable variation among the caste groups studied. The Nei genetic distances calculated from the 4 loci demonstrate that Khatri, Arora and Rajput are strongly clustered together and genetically they are closer to Brahmin than to Vaish and Scheduled Castes. Vaish emerge as a unique group showing maximum genetic distances with all other caste groups. The comparison of the present populations with our own data from two south Indian populations indicates that the tribal population of Soliga is distinct from the non-tribal populations, but the non-tribal south Indian series clusters closely with the main caste populations in north India.


Relationship of fertility to patterns of ovarian follicular development and associated hormonal profiles in dairy cows and heifers. Cooperative Regional Research Project.
Ovarian follicular development, hormonal patterns, and fertility were compared for growing and persistent follicles in 98 lactating dairy cows and in 89 heifers. Pregnancy rates were greater in animals that ovulated the first-wave dominant follicle while it was growing (GF) vs persistent (PF; for cows 54.2 vs 14.0%, P < .001; for heifers 62.0 vs 35.9%, P < .05). Follicles were larger in cows than in heifers (P < .05). Preovulatory growth rate (mm/d) for PF in cows was parallel to that of GF in both groups; in heifers, PF grew more slowly. At estrus, PF were larger than GF in cows and overall (P < .001), but not in heifers. Estradiol in plasma was greater (P < .05 in animals with PF than in those with GF before estrus (for 6 d in heifers, 8 d in cows). During d -6 through -2, progesterone in plasma tended to be lower (P = .12) in cows with PF than in heifers with PF. Pulse frequency of LH in plasma increased on d 7 in animals with GF and more frequent LH pulses continued through d 13 and 14 in animals with PF. After AI, progesterone in plasma did not differ between GF and PF, in either cows or heifers. However, among cows with GF, progesterone was greater (P < .01) by d 6 to 7 after estrus in pregnant than in nonpregnant cows. In summary, fertility was lower in animals that ovulated a persistent rather than a growing follicle, especially in lactating cows. Lower fertility in animals with PF was associated with prolonged increases in concentrations of LH and estradiol in plasma before estrus and ovulation.


The prevalence of autoantibodies in complex regional pain syndrome type I.
Autoimmunity has been suggested as one of the pathophysiologic mechanisms that may underlie complex regional pain syndrome (CRPS). Screening for antinuclear antibodies (ANA) is one of the diagnostic tests, which is usually performed if a person is suspected to have a systemic autoimmune disease. Antineuronal antibodies are autoantibodies directed against antigens in the central and/or peripheral nervous system. The aim of this study was to compare the prevalence of these antibodies in CRPS patients with the normal values of those antibodies in the healthy population. Twenty seven (33%) of the 82 CRPS patients of whom serum was available showed a positive ANA test. This prevalence is significantly higher than in the general population. Six patients (7.3%) showed a positive result for typical antineuronal antibodies. This proportion, however, does not deviate from that in the general population. Our findings suggest that autoantibodies may be associated with the pathophysiology of CRPS, at least in a subset of patients. Further research is needed into defining this subset and into the role of autoantibodies in the pathogenesis of CRPS.


Time course of humoral and cell-mediated immune responses to human papillomavirus type 16 in infected women.
The time course of cell-mediated and humoral immune responses was elucidated in eight women with human papillomavirus type 16 (HPV-16) infection by performing serial HPV-16 E6 and E7 cytotoxic T-lymphocyte (CTL) assays and HPV-16 virus-like particle (VLP) antibody analyses. Four subjects had a single incident of HPV-16 DNA detection, and four subjects had two periods of HPV-16 DNA detection. In two of the women in the latter group, the second episode of HPV-16 detection occurred in the presence of high titers of HPV-16 VLP antibody, bringing into question the protective role of humoral immunity in preventing repeated infection. However, all four subjects rapidly became HPV-16 DNA negative following the second detection of HPV-16 DNA, suggesting the presence of immunological memory. In addition, one subject rapidly became negative for HPV-16 DNA despite having no evidence of CTL or VLP antibody response prior to the second HPV-16 DNA detection, suggesting the presence of immunological responses at an undetectable level. Overall, seven of eight subjects (88%) had detectable HPV-16 E6 and/or E7 CTL responses and seven of eight women (88%) had detectable HPV-16 VLP antibody responses.


Tuning the magnetic properties of metal oxide nanocrystal heterostructures by cation exchange.
For three types of colloidal magnetic nanocrystals, we demonstrate that postsynthetic cation exchange enables tuning of the nanocrystal's magnetic properties and achieving characteristics not obtainable by conventional synthetic routes. While the cation exchange procedure, performed in solution phase approach, was restricted so far to chalcogenide based semiconductor nanocrystals, here ferrite-based nanocrystals were subjected to a Fe(2+) to Co(2+) cation exchange procedure. This allows tracing of the compositional modifications by systematic and detailed magnetic characterization. In homogeneous magnetite nanocrystals and in gold/magnetite core shell nanocrystals the cation exchange increases the coercivity field, the remanence magnetization, as well as the superparamagnetic blocking temperature. For core/shell nanoheterostructures a selective doping of either the shell or predominantly of the core with Co(2+) is demonstrated. By applying the cation exchange to FeO/CoFe(2)O(4) core/shell nanocrystals the Neél temperature of the core material is increased and exchange-bias effects are enhanced so that vertical shifts of the hysteresis loops are obtained which are superior to those in any other system.


Metalloproteases and gamma-secretase: new membrane partners regulating p75 neurotrophin receptor signaling?
Signaling by the p75 neurotrophin receptor (p75) has been implicated in diverse neuronal responses, including the control of neuronal survival versus death and axonal regeneration and growth cone collapse, involving p75 in different neuropathological conditions. There are different levels of complexity regulating p75-mediated signaling. First, p75 can interact with different ligands and co-receptors in the plasma membrane, forming tripartite complexes, whose activation result in different cellular outcomes. Moreover, it was recently described that trafficking capacities of p75 in neurons are regulating, in addition to p75 downstream interactions, also the sequential cleavage of p75. The proteolytical processing of p75 involves, first, a shedding event that releases a membrane-bound carboxiterminal fragment (p75-CTF), followed by a gamma-secretase mediated cleavage, generating a soluble intracellular domain (p75-ICD) with signaling capabilities. The first shedding event, generating a p75-CTF, is the key step to regulating the production of p75-ICD, and although the generation of p75-ICD is important for both p75-mediated control of neuronal survival and the control of neurite outgrowth, little is known how both cleavage events are regulated. In this review, we argue that both sheddases and gamma-secretase are key membrane components regulating p75-mediated signaling transduction; therefore, further attention should be paid to their roles as p75 signaling regulators.


Precursor recommendation for inorganic synthesis by machine learning materials similarity from scientific literature.
Synthesis prediction is a key accelerator for the rapid design of advanced materials. However, determining synthesis variables such as the choice of precursor materials is challenging for inorganic materials because the sequence of reactions during heating is not well understood. In this work, we use a knowledge base of 29,900 solid-state synthesis recipes, text-mined from the scientific literature, to automatically learn which precursors to recommend for the synthesis of a novel target material. The data-driven approach learns chemical similarity of materials and refers the synthesis of a new target to precedent synthesis procedures of similar materials, mimicking human synthesis design. When proposing five precursor sets for each of 2654 unseen test target materials, the recommendation strategy achieves a success rate of at least 82%. Our approach captures decades of heuristic synthesis data in a mathematical form, making it accessible for use in recommendation engines and autonomous laboratories.


Synthesis and activities of 5-substituted-2-(p-substituted phenyl)-1-dialkylaminomethyl benzimidazole derivatives.
Nine 1,2,5-trisubstituted benzimidazole derivatives were prepared and their structure have been elucidated by IR, NMR spectral data and elemental analyses. Analgesic activity of the compounds prepared was investigated in mice by modified KOSTER test. Anti-inflammatory activity of these compounds was investigated by a carregeenan-induced hind paw edema model in mice. Their antibacterial activities were examined against S. aureus, E. faecalis, E. coli, P. aeruginosa, and antifungal activity against three kinds of yeast-like fungi (C. albicans, C. parapsilosis, C. stellatoidea).


The qualities of attachment with significant others and self-compassion protect adolescents from non suicidal self-injury.
Nonsuicidal self-injury (NSSI) is a serious public health problem. Identifying the factors that could help prevent or reduce NSSI is important. The current study examined the protective roles of the perceived qualities of current attachment to significant others (i.e., mothers, fathers, and peers) and self-compassion in adolescent NSSI. The potential mediating effect of self-compassion in the relationships between attachment relationships with mothers, fathers, and peers and adolescent NSSI was also explored. Self-reported data on mother, father, and peer attachment (each included 3 dimensions; i.e., trust, communication, and closeness); self-compassion; and NSSI were collected from 658 secondary school students (59.9% male; Mage = 13.58 years). Participants with NSSI experiences scored significantly higher on the perceived qualities of current attachment with parents and self-compassion than those reporting no NSSI experience. Attachment with peers did not distinguish the NSSI group from the Non-NSSI group. Further mediation analyses indicated that self-compassion mediated the relationships of closeness with mothers, fathers (partially), and peers to NSSI as well as the relationship of peer communication to NSSI. Limitations of this study and implications regarding the protective roles of attachment and self-compassion in the prevention and intervention for NSSI are discussed. (PsycINFO Database Record


In vivo antitumor and immunomodulation activities of different molecular weight lambda-carrageenans from Chondrus ocellatus.
lambda-Carrageenan is a sulfated galactan isolated from some red algae and have been reported to have many kinds of biological activities. lambda-Carrageenan from Chondrus ocellatus, an important economic alga in China and many other parts of the world, was degraded by microwave, and obtained five products that have different molecular weight: 650, 240, 140, 15, 9.3 kDa. Analytical results confirmed that microwave degradation might not change the chemical components and structure of polysaccharides under certain condition. In this study, tumor-inhibiting activities, weight of immune organ, nature killer cells activity, lymphocyte proliferation ratio and pathological slice of spleen and tumor cells from the control group and lambda-carrageenan-treated mice of transplanted S180 and H22 tumor were investigated. The results indicated that the five lambda-carrageenan samples all showed antitumor and immunomodulation activities in different degree. Molecular weight of polysaccharides had notable effect on the activities. In addition, their antitumor and immunomodulation have some relevance and the five lambda-carrageenans probably inhibited tumor by means of activating the immunocompetence of the body. Among all the experiment results, samples with the highest activities are PC4 and PC5 whose molecular weight are 15 and 9.3 kDa.


Nonlinear Dynamics of Binge Drinking among U.S. High School Students in Grade 12: Cusp Catastrophe Modeling of National Survey Data.
Findings from cusp catastrophe modeling of binge drinking among college students in the United States (U.S.) and high school students in other countries (i.e., Japan) have advanced our understanding of alcohol abuse. No reported study has used the same method to investigate binge drinking among U.S. high school students, a high-risk population for alcohol abuse. In this study, we analyzed data for 12th graders (n = 1122) from the 2015 Monitoring the Future (MFT) Study with cusp catastrophe models. Guided by Kahneman's dual-system theory that integrates the theories of reasoned action and planned behavior, perceived alcohol harm (0-3, larger indicating less harm) was modeled as asymmetry variable (knowledge and beliefs), and drinking in social settings (contextual factors, 0 = no and 4 = always) as bifurcation variable to predict binge drinking in the past two weeks (0, 1, 2, 3 or more times). Analytical results indicated that a cusp model, depending on the method for parameter estimation could explain 36-88% of the variance in binge drinking while a linear model only explained up to 14%. Results from the indirect cusp modeling methods indicated that perceived alcohol harm and drinking in social settings both significantly predicted binge drinking. However, the estimated cusp point varied depending on the method for parameter estimation. In conclusion, the dynamics of binge drinking among U.S. high school students are nonlinear and discrete. Knowledge-based interventions to prevent binge drinking need to emphasize social and contextual factors that may trigger sudden behavior change to achieve greater intervention effect. To advance cusp catastrophe modeling, further research is needed to improve the method for parameter estimation.


Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug.
The combination of pomegranate seed oil and ketoprofen in nanoemulsions aiming to improve the antinociceptive effect was evaluated according to the writhing test and Complete Freud's Adjuvant induced paw inflammation in mice. The formulations showed adequate characteristics and improved ketoprofen's photostability against UVC radiation exposure. The dialysis bag technique showed that 100% of the drug was released from the nanoemulsions after 3h and the oil amount had no influence on the releasing. Furthermore, time- and dose-response curves were obtained to determine the antinociceptive effect of the formulations. In the post-test, the nanoemulsion containing ketoprofen significantly reduced abdominal constrictions in time-response curve, showing effect up to 12h while the free ketoprofen showed effect up to 3h. In addition, the blank nanoemulsion presented a reduction of abdominal constriction up to 1h of pre-treatment. Regarding the dose-response curve, the free ketoprofen presents effect at 0.5mg/Kg dose and nanoemulsion at 1.0mg/Kg dose. Time- and dose-response curves were performed to determine the antinociceptive effect in inflammatory pain. After the evaluation of mechanical allodynia testing at the Von Frey Hair, the free ketoprofen showed effect up to 6h while nanoemulsions presented effect up to 10h. Moreover, acute toxicity was performed with ALT and AST activity evaluations and urea levels. After 7 days of treatment, no toxic effects for nanoemulsions were found. In conclusion, ketoprofen-loaded pomegranate seed oil nanoemulsions presented adequate characteristics and a high antinociceptive activity in the animal models tested.


Cerebellar White Matter Abnormalities in Charcot-Marie-Tooth Disease: A Combined Volumetry and Diffusion Tensor Imaging Analysis.
Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary peripheral neuropathy. Brain volumetry and diffusion tensor imaging (DTI) were performed in 47 controls and 47 CMT patients with PMP22 duplication (n = 10), MFN2 (n = 15), GJB1 (n = 11), or NEFL mutations (n = 11) to investigate for structural changes in the cerebellum. Volume of cerebellar white matter (WM) was significantly reduced in CMT patients with NEFL mutations. Abnormal DTI findings were observed in the superior, middle, and inferior cerebellar peduncles, predominantly in NEFL mutations and partly in GJB1 mutations. Cerebellar ataxia was more prevalent in the NEFL mutation group (72.7%) than the GJB1 mutation group (9.1%) but was not observed in other genotypic subtypes, which indicates that structural cerebellar abnormalities were associated with the presence of cerebellar ataxia. However, NEFL and GJB1 mutations did not affect cerebellar gray matter (GM), and neither cerebellar GM nor WM abnormalities were observed in the PMP22 duplication or MFN2 mutation groups. We found structural evidence of cerebellar WM abnormalities in CMT patients with NEFL and GJB1 mutations and an association between cerebellar WM involvement and cerebellar ataxia in these genetic subtypes, especially in the NEFL subgroup. Therefore, we suggest that neuroimaging, such as MRI volumetry or DTI, for CMT patients could play an important role in detecting abnormalities of cerebellar WM.


Downy mildew (Peronospora parasitica) resistance genes in Arabidopsis vary in functional requirements for NDR1, EDS1, NPR1 and salicylic acid accumulation.
To better understand the genetic requirements for R gene-dependent defense activation in Arabidopsis, we tested the effect of several defense response mutants on resistance specified by eight RPP genes (for resistance to Peronospora parasitica) expressed in the Col-0 background. In most cases, resistance was not suppressed by a mutation in the SAR regulatory gene NPR1 or by expression of the NahG transgene. Thus, salicylic acid accumulation and NPR1 function are not necessary for resistance mediated by these RPP genes. In addition, resistance conferred by two of these genes, RPP7 and RPP8, was not significantly suppressed by mutations in either EDS1 or NDR1. RPP7 resistance was also not compromised by mutations in EIN2, JAR1 or COI1 which affect ethylene or jasmonic acid signaling. Double mutants were therefore tested. RPP7 and RPP8 were weakly suppressed in an eds1-2/ndr1-1 background, suggesting that these RPP genes operate additively through EDS1, NDR1 and as-yet-undefined signaling components. RPP7 was not compromised in coi1/npr1 or coi1/NahG backgrounds. These observations suggest that RPP7 initiates resistance through a novel signaling pathway that functions independently of salicylic acid accumulation or jasmonic acid response components.


Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition).
Diagnostic guidelines for Kawasaki Disease was revised to meet the present situation in 2002. This issue intends to explain new guidelines and their backgrounds. Major alterations are interpretation of cases with 4 or fewer febrile days shortened by early intravenous immunoglobulin treatment, and the clinical importance of atypical (incomplete, or suspected) cases.


Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes.
Chemical modification and inactivation of aminoglycosides by many different enzymes expressed in pathogenic bacteria are the main mechanisms of bacterial resistance to these antibiotics. In this work, we designed inhibitors that contain the 1,3-diamine pharmacophore shared by all aminoglycoside antibiotics that contain the 2-deoxystreptamine ring. A discovery library of molecules was prepared by attaching different side chains to both sides of the 1,3-diamine motif. Several of these diamines showed inhibitory activity toward two or three different representative aminoglycoside-modifying enzymes (AGMEs). These studies yielded the first non-carbohydrate inhibitor N-cyclohexyl-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound G,H) that is competitive with respect to the aminoglycoside binding to the enzyme aminoglycoside-2''-nucleotidyltransferase-Ia (ANT2''). Another diamine molecule N-[2-(3,4-dimethoxyphenyl)-ethyl]-N'-(3-dimethylamino-propyl)-propane-1,3-diamine (Compound H,I) was shown to be a competitive inhibitor of two separate enzymes (aminoglycoside-3'-phosphotransferase-IIIa (APH3') and ANT2'') with respect to metal-ATP. Thermodynamic and structural-binding properties of the complexes of APH3' with substrates and inhibitor were shown to be similar to each other, as determined by isothermal titration calorimetry and NMR spectroscopy.


Talking with a doctor during a visit elicits increases in systolic and diastolic blood pressure.
To investigate the impact of talking with doctors on blood pressure (BP) in outpatients. This study included 122 hypertensive and 78 normotensive outpatients. BP was measured initially in silence with oscillometric BP monitors three times at 1-min intervals as follows: pre-1, pre-2, and pre-3. BP was then measured with the same device immediately, at 3 min, and at 5 min after talking commenced as follows: during-1, during-3, and during-5. When talking stopped, BP was measured again as post-1, post-3, and post-5. The increments in BP and heart rate (HR) were the differences during and pre-3 values. Systolic blood pressure/diastolic blood pressure (SBP/DBP) increased significantly at 1 min during talking compared with pre-3 values. The maximum increment of SBP was 9.1 mmHg, occurring at 3 min and continuing up to 5 min during the talking stage. The maximum increment of DBP was 4.5 mmHg and that of HR was 2.7 bpm, both occurring at 1 min. When talking stopped, the SBP and DBP significantly decreased immediately. SBP at 5 min, DBP at 3 min, and HR at 1 min were similar to their pre-3 values. Logistic multifactor analysis showed that pre-SBP3 level (R=0.141, P=0.023) was an independent factor, but anxiety scale, age, sex, BMI, and hypertension history were not independent factors. The maximum SBP increment is 9.1 mmHg and DBP increment is 4.5 mmHg during 5 min of talking with doctor. Meanwhile, the increased SBP needs about 5 min to return to the baseline level.


Increased numbers of circulating basophil progenitors in atopic patients.
Recruitment of basophils to sites of homocytotropic antibody-mediated hypersensitivity reactions has been well documented in both experimental and clinical situations. Mechanisms underlying tissue basophil accumulation, however, remain unclear and may involve chemotaxis, cell proliferation, or both. We have recently reported the presence in human blood of circulating basophil/mast cell progenitors on the basis of histamine content of granulocyte colonies grown in methylcellulose. In the current studies we have analyzed the peripheral blood of 30 patients with atopy and 25 comparable control subjects for frequency of basophil/mast cell progenitors by analysis of the histamine content of individual granulocyte colonies. Forty percent of granulocyte colonies in cultures of atopic patients contained histamine in comparison to only 11% in cultures of control subjects (p less than 0.001). Histamine content per colony as well as mean histamine per cell in each colony was higher in granulocyte colonies of atopic subjects and could not be related to colony size or culture conditions. Granulocyte colony growth was enhanced by antigen-stimulated, peripheral blood lymphomononuclear cell--conditioned media of atopic patients. Histamine-positive colonies were found more frequently in active versus quiescent atopic disease (p less than 0.05). These results are consistent with the hypothesis that basophils accumulate at sites of allergic reactions at least in part by recruitment of progenitors from circulation and subsequent differentiation in situ in response to lymphokines. Further studies by use of hemopoietic assays could elucidate the contribution of basophil production to the development of allergic conditions.


GM wheat development in China: current status and challenges to commercialization.
Genetic modification facilitates research into fundamental questions of plant functional genomics and provides a route for developing novel commercial varieties. In 2008, significant financial resources were supplied by the Chinese government for research and development (R&D) into genetic modification of the major crop species. This project was aimed at providing an opportunity for crop improvement while accentuating the development of a safe, precise, and effective wheat genetic transformation system suitable for commercialization. The focus here is on one of the key crops included in this project, wheat, to provide an insight into the main transformation methods currently in use, the target traits of major importance, and the successful applications of wheat genetic improvement in China. Furthermore, the biosafety and regulatory issues of major concern and the strategies to produce 'clean' transgenic wheat plants will also be discussed. This commentary is intended to be a helpful insight into the production and commercialization of transgenic wheat in China and to put these activities into a global context.


Test-retest reliability and reproducibility of short-echo-time spectroscopic imaging of human brain at 3T.
A 1H magnetic resonance spectroscopic imaging study at 3T and short echo time was conducted to evaluate both the reproducibility, as measured by the interscan coefficient of variation (CV), and test-retest reliability, as measured by the intraclass correlation coefficient (ICC), of measurements of glutamate (Glu), combined glutamate and glutamine (Glx), myo-inositol (mI), N-acetylaspartate, creatine, and choline in 21 healthy subjects. The effect of partial volume correction on these measures and the relationship of reproducibility and reliability to data quality were also examined. A 1H magnetic resonance spectroscopic imaging slice was prescribed above the lateral ventricles and single repeat scans were performed within 30 min to minimize physiologic variability. Interscan CVs based on all the voxels varied from 0.05 to 0.07 for N-acetylaspartate, creatine, and choline to 0.10-0.13 for mI, Glu, and Glx. Findings on the reproducibility of gray and white matter estimates of N-acetylaspartate, creatine, and choline are consistent with previous studies using longer echo times, with CVs in the range of 0.02-0.04 and ICC in the range of 0.65-0.90. CVs for Glu, Glx, and mI are much lower than reported in previous studies at 1.5 T, while white matter mI (CV=0.04, ICC=0.93) and gray matter Glx (CV=0.04, ICC=0.68) demonstrated both high reproducibility and test-retest reliability.


Which disinfectant and where?
The introduction of a disinfection policy for a hospital and its supervision and control, are discussed. The need for total staff co-operation is highlighted with laboratory monitoring, an essential component to determine the success of the policy and to detect breakdowns in techniques.


A Robust Detection Algorithm for Infrared Maritime Small and Dim Targets.
Infrared maritime target detection is the key technology of maritime target search systems. However, infrared images generally have the defects of low signal-to-noise ratio and low resolution. At the same time, the maritime environment is complicated and changeable. Under the interference of islands, waves and other disturbances, the brightness of small dim targets is easily obscured, which makes them difficult to distinguish. This is difficult for traditional target detection algorithms to deal with. In order to solve these problems, through the analysis of infrared maritime images under a variety of sea conditions including small dim targets, this paper concludes that in infrared maritime images, small targets occupy very few pixels, often do not have any edge contour information, and the gray value and contrast values are very low. The background such as island and strong sea wave occupies a large number of pixels, with obvious texture features, and often has a high gray value. By deeply analyzing the difference between the target and the background, this paper proposes a detection algorithm (SRGM) for infrared small dim targets under different maritime background. Firstly, this algorithm proposes an efficient maritime background filter for the common background in the infrared maritime image. Firstly, the median filter based on the sensitive region selection is used to extract the image background accurately, and then the background is eliminated by image difference with the original image. In addition, this article analyzes the differences in gradient features between strong interference caused by the background and targets, proposes a small dim target extraction operator with two analysis factors that fit the target features perfectly and combines the adaptive threshold segmentation to realize the accurate extraction of the small dim target. The experimental results show that compared with the current popular small dim target detection algorithms, this paper has better performance for target detection in various maritime environments.


Drug Reprofiling to Identify Potential HIV-1 Protease Inhibitors.
The use of protease inhibitors in human immunodeficiency virus type 1 (HIV-1) treatment is limited by adverse effects, including metabolic complications. To address these challenges, efforts are underway in the pursuit of more potent and less toxic HIV-1 protease inhibitors. Repurposing existing drugs offers a promising avenue to expedite the drug discovery process, saving both time and costs compared to conventional de novo drug development. This study screened FDA-approved and investigational drugs in the DrugBank database for their potential as HIV-1 protease inhibitors. Molecular docking studies and cell-based assays, including anti-HIV-1 in vitro assays and XTT cell viability tests, were conducted to evaluate their efficacy. The study findings revealed that CBR003PS, an antibiotic currently in clinical use, and CBR013PS, an investigational drug for treating endometriosis and uterine fibroids, exhibited significant binding affinity to the HIV-1 protease with high stability. Their EC50 values, measured at 100% cell viability, were 9.4 nM and 36.6 nM, respectively. Furthermore, cell-based assays demonstrated that these two compounds showed promising results, with therapeutic indexes higher than 32. In summary, based on their favorable therapeutic indexes, CBR003PS and CBR013PS show potential for repurposing as HIV-1 protease inhibitors.


Preschool children generate quantity inferences from both words and pictures.
As children learn to communicate with others, they must develop an understanding of the principles that underlie human communication. Recent evidence suggests that adults expect communicative principles to govern all forms of communication, not just language, but evidence about children's ability to do so is sparse. This study investigated whether preschool children expect both pictures and words to adhere to the communicative principle of quantity using a simple matched paradigm. Children (N = 293) aged of 3 to 5 years (52.5% male and 47.5% female; majority White with college-educated mothers) participated. Results show that children as young as 3.5 years can use the communicative principle of quantity to infer meaning across verbal and pictorial alternatives.


Improved transmission model for metal-dielectric-metal plasmonic waveguides with stub structure.
We present an improved analytical model describing transmittance of a metal-dielectric-metal (MDM) waveguide coupled to an arbitrary number of stubs. The model is built on the well-known analogy between MDM waveguides and microwave transmission lines. This analogy allows one to establish equivalent networks for different MDM-waveguide geometries and to calculate their optical transmission spectra using standard analytical tools of transmission-line theory. A substantial advantage of our model compared to earlier works is that it precisely incorporates the dissipation of surface plasmon polaritons resulting from ohmic losses inside any metal at optical frequencies. We derive analytical expressions for transmittance of MDM waveguides coupled to single and double stubs as well as to N identical stubs with a periodic arrangement. We show that certain phase-matching conditions must be satisfied to provide opt al filtering characteristics for such waveguides. To check the accuracy of our model, its results are compared with numerical data obtained from the full-blown finite-difference time-domain simulations. Close agreement between the two suggests that our analytical model is suitable for rapid design optimization of MDM-waveguide-based compact photonic devices.


The microanatomy of the distal tubules, collecting tubules and collecting ducts of the starling kidney.
Light and electron microscopic techniques were employed to characterise the various cell types found in the distal tubules, collecting tubules and collecting ducts in the kidneys of wild starlings (Sturnus vulgaris). There was a gradual change in cell characteristics along the length of the distal tubule. A short transition zone was identified, between the distal tubule and the intralobular collecting tubule, which contained cell types that were characteristic of both segments. The end of the distal tubule was marked by the appearance of scattered dark cells and occasional mucin-secreting cells. The dark cells were electron-dense and usually possessed many microvesicles in the subapical region; there were also numerous, stubby apical microprocesses in many cases. In the basal regions of these cells were many, short, regular infoldings of the plasma membrane. The initial part of the intralobular collecting tubule was lined by approximately equal numbers of dark and mucin-secreting cells. However, as the tubule progressed towards the lobular periphery, the number of dark cells declined. Few dark cells were observed in the perilobular collecting ducts and none in the medullary ducts which were lined by columnar mucin-secreting cells. The mucin-secreting cells possessed a prominent supranuclear Golgi apparatus and apical vacuoles containing a strongly PAS- and alcian blue-positive mucigen. Critical electrolyte concentration methods, using alcian blue in the presence of magnesium chloride, indicated that the mucigen contained large amounts of a strongly sulphated component, but was probably of a mixed nature. The dark cells were slightly PAS-positive but only very weakly alcian blue-positive at the cell apices. The roles of the various cell types were discussed in relation to the uric acid excretion habit of birds.


Early social experience affects behavioral and physiological responsiveness to stressful conditions in infant rhesus macaques (Macaca mulatta).
Studies on early development have demonstrated the profound effects of early social experience on the behavioral development and physiology of young rhesus macaques. Given these relationships, we hypothesized that rhesus macaques exposed to different nursery-rearing conditions may develop unique biobehavioral profiles. If this is true, the assessment of temperament may allow us to pinpoint successful rearing environments, thus improving the overall health of nonhuman primates that are raised in captive environments. We conducted biobehavioral assessments in order to examine differences in the development of infants raised under four different peer-rearing conditions (continuous pairing (CP), intermittent pairing, CP with partner rotation, and intermittent rotational pairing) and compared these animals with data from a mother-reared control group. Overall, continuous rotationally paired animals were most similar to mother-reared controls on most behavioral and temperament measures, suggesting that more socially complex rearing environments (greater number of social partners) favor a more active behavioral style. Cortisol profiles of mother-reared controls were similar to both CP groups, and these three groups had higher cortisol concentrations than the intermittent rotational-pairing group. In addition, intermittently paired infants displayed a significantly higher frequency of self-stroke behavior during a human intruder challenge, an abnormal behavior also known as floating limb which has been shown to be a precursor of self-biting. Overall, the data are consistent with the idea that social complexity in the nursery, as operationalized in our continuous rotational pairing, leads to a biobehavioral profile that is most similar to that of infants raised by their mothers in large, socially complex, cages.


Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility.
To assess the importance of the plasminogen activator (PA) system and vascular endothelial growth factor (VEGF) in subfertility. Review. Two university IVF centers. Systematic literature search (MEDLINE, Science Direct, and bibliographies of published works). The PA system in the male is involved in the passage of spermatozoa precursor cells over the blood-testis barrier, the epididymal maturation of spermatozoa, the modifications of the sperm surface for capacitation, the acrosome reaction and zona pellucida attachment, and finally the facilitation of spermatozoa to move into the fallopian tubes. In the female, the PA system plays a role during ovulation in the release of the oocyte from the follicle, the facilitation of oocyte movement into the fallopian tubes, and the extracellular matrix degradation important for angiogenesis in the ovary. The function of VEGF during fertilization is largely unknown. It has been suggested that VEGF is important for the fluid and proteins in semen and fluid secretion in the female genital tract, thereby influencing sperm motility and survival. The latter could be due to an effect of VEGF on testicular microvasculature, through which an adequate microenvironment for spermatogenesis is provided. In the female, VEGF is involved in the regulation of the cyclic ovarian angiogenesis, the development and/or selection of follicles, the accumulation of follicular fluid, and corpus luteum angiogenesis. The role of the PA system and VEGF in reproduction most likely is of great interest. However, much of the data are derived from experimental animal studies. So far, information on the importance of these systems in humans is scarcely investigated. Therefore, further research is required to elucidate the role of the PA system and VEGF in the pathogenesis and prevention of male and female subfertility. Eventually, this will contribute to the improvement of the diagnosis of subfertility and may possibly lead to targeted therapeutic management of subfertility.


Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.
Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCβ, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.


Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches.
The recent approval of two immune checkpoint inhibitors for the treatment of malignant melanoma has sparked great interest by physicians and basic scientists searching for novel therapeutics for GI cancer. Chronic inflammation is recognised as a major risk factor for the development of hepatocellular carcinoma (HCC) and makes this type of cancer a potentially ideal target for an immune based treatment approach. Further evidence for a critical role of immune responses in patients with HCC is derived from the fact that immune signatures and profiles predict patients' outcome as well as the fact that tumour-induced spontaneous antitumour immunity can be detected. In addition ablative therapies can lead to changes in the number, phenotype and function of different immune cell subsets, which correlate with patients' survival. Various HCC-specific mouse models have been developed, which improve our understanding of hepatocarcinogenesis and tumour-immune cell interactions, and lead to the development of novel immune based treatment approaches, which are currently being evaluated in preclinical and in early clinical settings. Immune checkpoint blockade along with adoptive immune cell therapy and vaccine approaches are currently being evaluated either alone or in combination with other treatments. Here, we provide an overview for the rationale of immunotherapy in HCC, summarise ongoing studies and provide a perspective for immune based approaches in patients with HCC.


Hypothyroidism and wound healing: occurrence after head and neck radiation and surgery.
A retrospective five-year review of patients treated for cancer of the larynx disclosed a high prevalence of hypothyroidism after combined therapy. A total of 29 patients were studied. Seven (24%) of the 29 patients had hypothyroidism develop in the posttreatment period (zero to two years). Two (22%) of the nine patients treated with a combination of surgery and radiation had hypothyroidism develop. An additional ten patients treated with radiation alone remained clinically euthyroid, and no thyroid function tests were performed. Of the five patients who became hypothyroid after treatment with a combination of surgery and radiation, two had fistulae develop that were resistant to intensive local care. They closed promptly after treatment of the hypothyroidism. Of the two patients who had hypothyroidism develop after surgery alone, one had fistulae develop that were resistant to local cae, but responsive to thyroid hormone. These patients should have thyroid function tests done in the early postoperative period, and those found to be hypothyroid should be treated promptly.


[Coronary revascularization in the geriatric patient].
In order to determine the current status of coronary revascularization in the elderly, we studied 102 patients aged 65 to 77 years (mean 68 years) who had surgery at the Instituto Nacional de Cardiología "Ignacio Chávez". Seventy eight (76.4%) were male and 24 (23.5%) female. The coronary risk factors were cigarette smoking, systemic arterial hypertension and familiar history of coronary heart disease. Fifty five patients (54%) had myocardial infarction prior to surgery and in 29 (28.4%) the time between the ischemic event and surgery was less than one year. Ninety Patients (88.2%) presented with unstable and 12 (11.7%) with stable angina. Ejection fraction was less than 40% en 32 patients (31%). Coronary angiograms showed one vessel disease in 5 cases (4.9%), two vessel involvement in 29 (28.4%), three vessel lesions in 56 (55.8%) and left main coronary artery in 12 (11.7%). The patients underwent a mean of 2.1 bypasses (range 1 to 4). Perioperative mortality was 10.7%. Actuarial survival and angina pectoris relapse were 80 and 24% respectively at 6 years follow-up. We conclude that old age does not rule-out surgery for coronary heart disease.


Population genetics of sporophytic self-incompatibility in Senecio squalidus L. (Asteraceae) II: a spatial autocorrelation approach to determining mating behaviour in the presence of low S allele diversity.
We recently estimated that as few as six S alleles represent the extent of S locus diversity in a British population of the self-incompatible (SI) coloniser Senecio squalidus (Oxford Ragwort). Despite the predicted constraints to mating imposed by such a low number of S alleles, S. squalidus maintains a strong sporophytic self-incompatibility (SSI) system and there is no evidence for a breakdown of SSI or any obvious negative reproductive consequences for this highly successful coloniser. The present paper assesses mating behaviour in an Oxford S. squalidus population through observations of its effect on spatial patterns of genetic diversity and thus the extent to which it is responsible for ameliorating the potentially detrimental reproductive consequences of low S allele diversity in British S. squalidus. A spatial autocorrelation (SA) treatment of S locus and allozyme polymorphism data for four loci indicates that mating events regularly occur at all the distance classes examined from 60 to 480 m throughout the entire sample population. Less SA is observed for S locus data than for allozyme data in accordance with the hypothesis that SSI and low diversity at the S locus are driving these large-scale mating events. The limited population structure at small distances of 60 m and less observed for SA analysis of the Me-2 locus and by F-statistics for all the allozyme data, is evidence of some local relatedness due to limited seed and pollen dispersal in S. squalidus. However, the overall impression of mating dynamics in this S. squalidus population is that of ample potential mating opportunities with many individuals at large population scales, indicating that reproductive success is not seriously affected by few S alleles available for mating interactions.


Overweight and obesity prevalence in Israel: findings of the first national health and nutrition survey (MABAT).
The prevalence of obesity has increased considerably in many countries in recent decades. To describe the prevalence of overweight and obesity in the Israeli population, based on findings of the first national health and nutrition survey (MABAT). This cross-sectional survey was carried out during 1999-2000. MABAT is based on a representative sample (n = 3,246) of the general Israeli population aged 25-64 years. The current study population comprised those with complete data on measured weight and height (n = 2,781). Participants were interviewed in person and had their weight and height measured by the interviewer. Over 50% of the study participants were women (n = 1,410); 76% were Jews and 24% Arabs. Most participants had an education of at least 12 years (72%). Body mass index > or = 30.0 was more prevalent in women compared to men (P < 0.001) in both population groups (Jews and Arabs). Obesity rates increased with age and reached 22.4% for men and 40.4% for women aged 55-64 years. Lower education was associated with higher obesity rates, with lowest rates observed for Jewish women with an academic education (13.6%) and highest rates observed for Arab women with a basic education (57.3%). Multiple logistic regression analyses showed age to be a significant risk factor in men. Age, education and origin (Arab, and the former Soviet Union for Jews) were significant risk factors for obesity in women. Obesity rates in Israel are high and comparable to those in the United States. Of special concern is the subgroup of older Arab women (55-64 years), whose obesity rates reached 70%.


Chemically attenuated larvae of S. mansoni as a novel tool in schistosomiasis research: 2. Chemical attenuation of cercariae by diimidoesters.
A novel approach to chemically attenuate cercariae of S. mansoni is presented. The method utilizes the biologically active surface proteins/glycoproteins which are essential for the survival of the organism as a target for inactivation. The inactivation was achieved by reaction with 0.01 M dimethyl adipimidate, dimethyl pimelimidate or dimethyl suberimidate at pH 8.5. The cercariae lost their viability, but retained the ability to exclude trypan blue for up to 2 years when stored at 4 degrees C in a manner similar to live cercariae and in contrast to dead cercariae which took up the dye immediately. In addition, the attenuated cercariae reacted with monoclonal and polyclonal antischistosome antibodies in an indirect immunofluorescence assay indicating the retention and preservation of surface antigens after attenuation. The immunochemical reactivity of the attenuated cercariae was preserved after storage for 2 years at 4 degrees C as shown by reaction with antisera from infected mice and rats in IIF assay. Attenuated cercariae revealed the presence of antischistosome antibodies as early as one week after infection in mice and rats. The presence of receptors for the Fc portion of human IgG on the attenuated cercariae interfered in their use as an immunodiagnostic reagent for human schistosomiasis. The attenuated cercariae were also used to screen cultures for monoclonal antischistosome antibodies. Preliminary results indicated that immunization with attenuated cercariae was capable of imparting protective immunity in mice.


Change in explicit and implicit motivation toward physical activity and sedentary behavior in pulmonary rehabilitation and associations with postrehabilitation behaviors.
The aim of this study was twofold: (a) to determine whether Theory of Planned Behavior (TPB) variables and implicit attitudes toward physical activity and sedentary behavior would change during a 5-week pulmonary rehabilitation (PR) program, and (b) to investigate the relationships between behavioral intentions, implicit attitudes, physical activity, and sedentary behavior in postrehabilitation. Out of 142 patients with respiratory disease included in this study, 119 completed 2 questionnaires measuring TPB variables with regard to physical activity and sedentary behavior, and an Implicit Association Test (IAT) measuring implicit attitudes toward physical activity in contrast to sedentary behavior. The TPB questionnaires and the IAT were administered at the beginning (Time 1) and the end of the program (Time 2). Six months after the program (Time 3), 62 patients provided self-reported measures of their recreational physical activity and screen-based, leisure-time sedentary behavior. Over the course of pulmonary rehabilitation, perceived behavioral control and intentions toward physical activity increased, as did social norms and perceived behavioral control toward sedentary behavior; implicit attitudes were also more positive toward physical activity. Implicit attitudes at the end of PR (Time 2) were significantly associated with postrehabilitation physical activity (Time 3). TPB variables toward physical activity and sedentary behavior as well as implicit attitudes were enhanced during PR. At 6 months, implicit attitudes were significantly associated with physical activity. These results suggest that motivation, particularly implicit attitudes, should be targeted in future behavioral interventions in order to optimize the effects of rehabilitation on physical activity maintenance. (PsycINFO Database Record


A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer.
Use of the fourth-generation oral fluoropyrimidine S-1 together with gemcitabine has shown striking anticancer effects. In this single-arm phase I trial of preoperative combination therapy using gemcitabine and S-1 concurrently with radiotherapy, we verified the safety and feasibility and determined the maximum-tolerated dose of each drug in patients with resectable pancreatic cancer. A standard 3+3 dose escalation scheme was used. Patients with cytologically or histologically proven resectable pancreatic ductal adenocarcinoma were administered 30-min intravenous gemcitabine infusions on days 1, 8, 22, and 29 and S-1 orally on days 1-5, 8-12, 22-26, and 29-33. A total radiation dose of 50.4 Gy (1.8 Gy/day, 5 times per week, 28 fractions) was concurrently delivered. Surgical exploration was scheduled 4-7 weeks after the final radiation fraction. Twenty-one patients were enrolled. No treatment-related deaths occurred during this study. Recommended doses were determined to be 80 mg/m(2) of S-1 daily and 1,000 mg/m(2) of gemcitabine. CA19-9 was reduced to <50 % of baseline values in 12 (75 %) of 16 measurable patients. Nineteen of 21 enrolled patients successfully underwent surgical resection. Preoperative chemoradiotherapy consisting of gemcitabine and S-1 concurrent with full-dose radiation is feasible and well tolerated.


Multiple mild traumatic brain injury in the rat produces persistent pathological alterations in the brain.
Multiple mild traumatic brain injury (mmTBI), in certain cases, produces persistent symptoms. However, the molecular mechanisms underlying these symptoms remain unclear. Here, we demonstrate extended pathological changes in the rat brain following mmTBI. Using the lateral fluid percussion (LFP) technique we exposed adult male Wistar rats to a mild TBI (mTBI) once a week for four weeks and compared them to surgical shams. At 90days following the last TBI or sham procedure the animals were cognitively tested in the Morris Water Maze (MWM), euthanized, and the brains removed for immunohistochemistry. At 90days following the last mTBI, NRF-2 staining was significantly decreased in the hilus of the hippocampus and cortex on the injured side, but did not significantly differ from shams on the un-injured side. CD68 positive microglia were significantly increased in the ipsilateral corpus callosum, cortex, and internal capsule of injured animals. Reactive astrocytosis, determined by increased GFAP staining, was also evident in the corpus callosum, cortex, internal capsule and thalamus on the injured side. Interestingly, the corpus callosum thickness at the midline was decreased in injured animals and had evident demyelination when compared to sham animals. Despite these findings, there were no significant differences in neurological assessments at 90days following the last injury. In MWM testing there were not significant differences in the training phase, the time spent in the thigmotaxia zone, or the target quadrant during the probe trial. However, there were significant differences between shams and injured animals in platform zone crossings during the probe trial. These results demonstrate that repetitive head trauma may produce persistent, long-term pathological alterations in brain architecture that may be difficult to detect using standard cognitive and neurological assessments.


Simultaneous X-ray fluorescence and scanning X-ray diffraction microscopy at the Australian Synchrotron XFM beamline.
Owing to its extreme sensitivity, quantitative mapping of elemental distributions via X-ray fluorescence microscopy (XFM) has become a key microanalytical technique. The recent realisation of scanning X-ray diffraction microscopy (SXDM) meanwhile provides an avenue for quantitative super-resolved ultra-structural visualization. The similarity of their experimental geometries indicates excellent prospects for simultaneous acquisition. Here, in both step- and fly-scanning modes, robust, simultaneous XFM-SXDM is demonstrated.


A tuning fork gyroscope with drive-sense orthogonal thin-walled holes for high sensitivity.
A tuning fork gyroscope (TFG) with orthogonal thin-walled round holes in the driving and sensing directions is proposed to improve sensitivity. The thin walls formed by through holes produce stress concentration, transforming the small displacement of tuning fork vibration into a large concentrated strain. When piezoelectric excitation or detection is carried out here, the driving vibration displacement and detection output voltage can be increased, thereby improving sensitivity. Besides, quadrature coupling can be suppressed because the orthogonal holes make the optimal excitation and detection positions in different planes. The finite element method is used to verify the benefits of the holes, and the parameters are optimized for better performance. The experimental results show that the sensitivity of the prototype gyroscope with a driving frequency of 890.68 Hz is 100.32 mV/(°/s) under open-loop driving and detection, and the rotation rate can be resolved at least 0.016 (°/s)/Hz, which is about 6.7 times better than that of the conventional TFG. In addition, the quadrature error is reduced by 2.7 times. The gyroscope has a simple structure, high reliability, and effectively improves sensitivity, which is helpful to guide the optimization of piezoelectric gyroscopes and derived MEMS gyroscopes.


Regionally nested patterns of fish assemblages in floodplain lakes of the Magdalena river (Colombia).
We investigated if fish assemblages in neotropical floodplain lakes (cienagas) exhibit nestedness, and thus offer support to the managers of natural resources of the area for their decision making. The location was floodplain lakes of the middle section of the Magdalena river, Colombia. We applied the nested subset analysis for the series of 30 cienagas (27 connected to the main river and three isolated). All fish were identified taxonomically in the field and the matrix for presence-absence in all the lakes was used for the study of the pattern of nestedness. The most diverse order was Characiformes (20 species), followed by Siluriformes (19 species). Characidae and Loricaridae were the richest families. The species found in all the lakes studied were migratory species (17), and sedentary species (33). Two species (Caquetaia kraussii and Cyphocharax magdalenae) were widespread across the cienagas archipelago (100% of incidence). Nestedness analysis showed that the distribution of species over the spatial gradient studied (840 km) is significantly nested. The cienagas deemed the most hospitable were Simiti, El Llanito, and Canaletal. Roughly, 13 out of the 50 species caught show markedly idiosyncratic distributions. The resulting dataset showed a strong pattern of nestedness in the distribution of Magdalenese fishes, and differed significantly from random species assemblages. Out of all the measurements taken in the cienagas, only the size (area) and local richness are significantly related to the range of order of nested subset patterns (r=-0.59 and -0.90, respectively, at p < 0.01). Differential species extinction is suggested as the cause of a nested species assemblage, when the reorganized matrix of species occurring in habitat islands is correlated with the island area. Our results are consistent with this hypothesis.


Normative values of short-term heart rate variability in a cross-sectional study of a Danish population. The DanFunD study.
The autonomic nervous system includes parasympathetic and sympathetic components that monitor and regulate most of the bodily functions and play a central role in the physiology and homeostasis of the human body. Heart rate variability is a non-invasive tool for quantification of rhythmic fluctuations in heart rate that reflects the function of the autonomic nervous system. The study aims to describe the heart rate variability distribution in the general population, stratified in sex and age groups, which is currently insufficiently described. A cross-sectional population-based study recruited participants in 10 municipalities in the western part of the greater Copenhagen area in Denmark, including 6891 men and women aged 18-72 years (participation rate was 29.5%). Short-term heart rate variability measures were obtained and related to age and gender. Both time and frequency domain measures showed a huge variation in the different sex and age groups. Women had a higher median heart rate than men, and the association with age was U-shaped. Measures indicating a predominance of the parasympathetic component in relation to the sympathetic component were more frequent in women and younger age groups. Both sex and age influence the heart rate variability in this adult Danish population. Therefore, our age- and sex-related reference values of heart rate variability in the time and frequency domain should be used in further epidemiological and clinical research.


Monoclonal antibody-navigated carbon-encapsulated iron nanoparticles used for MRI-based tracking integrin receptors in murine melanoma.
Integrin beta-3 is a cell adhesion molecule that mediate cell-to-cell and cell-to-extracellular matrix communication. The major goal of this study was to explore melanoma cells (B16F10) based upon specific direct targeting of the β3 subunit (CD61) in the integrin αvβ3 receptor using carbon-encapsulated iron nanoparticles decorated with monoclonal antibodies (Fe@C-CONH-anti-CD61 and Fe@C-(CH2)2-CONH-anti-CD61). Both melanoma cells treated with nanoparticles as well as C57BL/6 mice bearing syngeneic B16-F10 tumors intravenously injected with nanoparticles were tested in preclinical MRI studies. The as-synthesized carbon-encapsulated iron nanoparticles functionalized with CD61 monoclonal antibodies have been successfully used as a novel targeted contrast agent for MRI-based tracking melanoma cells expressing the β3 subunit of the integrin αvβ3 receptor.


Bimekizumab treatment in biologic DMARD-naïve patients with active psoriatic arthritis: 52-week efficacy and safety results from the phase III, randomised, placebo-controlled, active reference BE OPTIMAL study.
Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. BKZ treatment has demonstrated superior efficacy versus placebo (PBO) at Week 16 in biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active psoriatic arthritis (PsA). Here, we report long-term efficacy and safety to Week 52. BE OPTIMAL comprised a 16-week, double-blind, PBO-controlled period, then 36 weeks treatment-blind. Patients were randomised 3:2:1 to subcutaneous BKZ 160 mg every 4 weeks, PBO with switch to BKZ at Week 16, or reference arm (adalimumab (ADA) 40 mg every 2 weeks). Efficacy outcomes included the American College of Rheumatology (ACR) response criteria 20/50/70, Psoriasis Area and Severity Index (PASI) 75/90/100 in patients with baseline psoriasis affecting ≥3% body surface area and minimal disease activity (MDA); non-responder imputation. ACR20/50/70, PASI75/90/100 and MDA responses were sustained with BKZ to Week 52, consistent with results observed at Week 16. Patients who switched to BKZ at Week 16 demonstrated improvements in efficacy with similar results to BKZ-randomised patients by Week 52.To Week 52, 555/702 (79.1%) patients had ≥1 treatment-emergent adverse event (TEAE) during BKZ treatment; 113/140 (80.7%) on ADA. On BKZ, 46 (6.6%) patients had serious TEAEs. 54 (7.7%) Candida infections occurred during BKZ treatment and 1 (0.7%) during ADA; all cases were localised and non-serious. One death occurred in a BKZ-treated patient, unrelated to treatment. The efficacy of BKZ in bDMARD-naïve patients with PsA was sustained from Week 16 to Week 52. BKZ was well tolerated with no new safety signals observed. NCT03895203.


Healthy lifestyle counteracts the risk effect of genetic factors on incident gout: a large population-based longitudinal study.
Risk genes linked to the development of gout have been identified, and lifestyle factors are related to gout risk. It remains unclear whether healthy lifestyle factors can mitigate the genetic risk of gout. Therefore, we aimed to explore whether and to what extent a healthy lifestyle can mitigate the risk of gout related to genetic factors. Within the UK Biobank, 416,481 gout-free participants (aged 37-74) were identified at baseline. Polygenic risk for gout was assessed and categorized as low (lowest tertile), middle (tertile 2), and high (highest tertile). Healthy lifestyle factors included no/moderate alcohol consumption, no smoking, physical activity, and a healthy diet. Participants were categorized into three groups according to their number of healthy lifestyle factors: unfavorable (0 or 1), intermediate (any 2), and favorable (3 or 4). Data were analyzed using Cox proportional hazard models. Over the follow-up (median: 12.1 years), 6206 participants developed gout. Compared to low genetic risk, the hazard ratios (HRs) and 95% confidence intervals (CIs) of gout was 1.44 (1.35-1.54) for middle and 1.77 (1.66-1.89) for high genetic risk. The HRs (95% CIs) of gout were 0.63 (0.59-0.67) for a favorable lifestyle and 0.79 (0.75-0.85) for an intermediate lifestyle, compared to an unfavorable lifestyle. In joint effect analysis, compared to participants with low genetic predisposition and a favorable lifestyle, the HRs (95% CIs) of gout were 2.39 (2.12-2.70)/3.12 (2.79-3.52) in those with middle and high genetic predisposition plus unfavorable lifestyle profiles, and 1.53 (1.35-1.74)/1.98 (1.75-2.24) for those with middle and high genetic predisposition plus favorable lifestyle profiles, respectively. Moreover, compared to an unfavorable lifestyle, the HRs of gout related to a favorable lifestyle was 0.64 (95% CI, 0.56-0.73) for low genetic risk, 0.65 (95% CI, 0.58-0.72) for middle genetic risk, and 0.62 (95% CI, 0.57-0.69) for high genetic risk. There was a significant additive interaction between unfavorable lifestyle and high genetic risk on gout. Healthy lifestyle was associated with a lower risk of gout and may attenuate the risk of gout related to genetic factors by almost a third.


Phylogenetic diversity of bacterial and archaeal communities in the anoxic zone of the Cariaco Basin.
Microbial community samples were collected from the anoxic zone of the Cariaco Basin at depths of 320, 500, and 1,310 m on a November 1996 cruise and were used to construct 16S ribosomal DNA libraries. Of 60 nonchimeric sequences in the 320-m library, 56 belonged to the epsilon subdivision of the Proteobacteria (epsilon-Proteobacteria) and 53 were closely related to ectosymbionts of Rimicaris exoculata and Alvinella pompejana, which are referred to here as epsilon symbiont relatives (ESR). The 500-m library contained sequences affiliated with the fibrobacteria, the Flexibacter-Cytophaga-Bacteroides division, the division Verrucomicrobia, the division Proteobacteria, and the OP3 candidate division. The Proteobacteria included members of the gamma, delta, epsilon and new candidate subdivisions, and gamma-proteobacterial sequences were dominant (25.6%) among the proteobacterial sequences. As in the 320-m library, the majority of the epsilon-proteobacteria belonged to the ESR group. The genus Fibrobacter and its relatives were the second largest group in the library (23.6%), followed by the delta-proteobacteria and the epsilon-proteobacteria. The 1,310-m library had the greatest diversity; 59 nonchimeric clones in the library contained 30 unique sequences belonging to the planctomycetes, the fibrobacteria, the Flexibacter-Cytophaga-Bacteroides division, the Proteobacteria, and the OP3 and OP8 candidate divisions. The proteobacteria included members of new candidate subdivisions and the beta, gamma, delta, and epsilon-subdivisions. ESR sequences were still present in the 1,310-m library but in a much lower proportion (8.5%). One archaeal sequence was present in the 500-m library (2% of all microorganisms in the library), and eight archaeal sequences were present in the 1,310-m library (13.6%). All archaeal sequences fell into two groups; two clones in the 1,310-m library belonged to the kingdom Crenarchaeota and the remaining sequences in both libraries belonged to the kingdom Euryarchaeota. The latter group appears to be related to the Eel-TA1f2 sequence, which belongs to an archaeon suggested to be able to oxidize methane anaerobically. Based on phylogenetic inferences and measurements of dark CO(2) fixation, we hypothesized that (i) the ESR are autotrophic anaerobic sulfide oxidizers, (ii) sulfate reduction and fermentative metabolism may be carried out by a large number of bacteria in the 500- and 1,310-m libraries, and (iii) members of the Euryarchaeota found in relatively large numbers in the 1,310-m library may be involved in anaerobic methane oxidation. Overall, the composition of microbial communities from the Cariaco Basin resembles the compositions of communities from several anaerobic sediments, supporting the hypothesis that the Cariaco Basin water column is similar to anaerobic sediments.


Vitamin D3 toxicity in dairy cows.
Large parenteral doses of vitamin D3 (15 to 17.5 x 10(6) IU vitamin D3) were associated with prolonged hypercalcemia, hyperphosphatemia, and large increases of vitamin D3 and its metabolites in the blood plasma of nonlactating nonpregnant and pregnant Jersey cows. Calcium concentrations 1 day postpartum were higher in cows treated with vitamin D3 about 32 days prepartum (8.8 mg/100 ml) than in control cows (5.5 mg/100 ml). None of the cows treated with vitamin D3 showed signs of milk fever during the peripartal period; however, 22% of the control cows developed clinical signs of milk fever during this period. Signs of vitamin D3 toxicity were not observed in nonlactating nonpregnant cows; however, pregnant cows commonly developed severe signs of vitamin D3 toxicity and 10 of 17 cows died. There was widespread metastatic calcification in the cows that died. Because of the extreme toxicity of vitamin D3 in pregnant Jersey cows and the low margin of safety between doses of vitamin D3 that prevent milk fever and doses that induce milk fever, we concluded that vitamin D3 cannot be used practically to prevent milk fever when injected several weeks prepartum.


The efficacy of laser therapy in wound repair: a meta-analysis of the literature.
We determined the overall effects of laser therapy on tissue healing by aggregating the literature and subjecting studies meeting the inclusion and exclusion criteria to statistical meta-analysis. Low-level laser therapy (LLLT) devices have been in use since the mid sixties, but their therapeutic value remains doubtful, as the literature seems replete with conflicting findings. Pertinent original research papers were gathered from library sources, online databases and secondary sources. The papers were screened and coded; those meeting every inclusion and exclusion criterion were subjected to meta-analysis, using Cohen's d. statistic to determine the treatment effect size of each study. Twenty-four studies with 31 effect sizes met the stringent inclusion and exclusion criteria. The overall mean effect of laser therapy on wound healing was highly significant (d = +2.22). Sub-analyses of the data revealed significant positive effects on wound healing in animal experiments (d = +1.97) as well as human clinical studies (d = +0.54). The analysis further revealed significant positive effects on specific indices of healing, for example, acceleration of inflammation (d = +4.45); augmentation of collagen synthesis (d = +1.80); increased tensile strength (d = +2.37), reduced healing time (d = +3.24); and diminution of wound size (d = +0.55). The Fail-Safe number associated with the overall effect of laser therapy was 509; a high number representing the number of additional studies-in which laser therapy has negative or no effect on wound healing-required to negate the overall large effect size of +2.22. The corresponding Fail-Safe number for clinical studies was 22. We conclude that laser therapy is an effective tool for promoting wound repair.


Knee and ankle range of motion during stepping down in elderly compared to young men.
A major factor limiting mobility in elderly subjects is their difficulty with descending steps but the physiological and biomechanical basis of this problem is not well understood. To address this question we have compared the kinematics of stepping down in six elderly male subjects and six weight- and height-matched younger subjects. Five reflective markers were positioned on the lower limbs and subjects were filmed stepping down from four heights (200, 250, 300, and 335 mm). Maximum angular displacements for the knee and ankle of the supporting limb were expressed as a percentage of each subject's passive range of motion (ROM). Time spent in 'foot flat' during single support was also compared. The results show the elderly subjects sustained dorsiflexion and a 'foot flat' position of the support limb for a significantly ( P<0.05) longer period than the young (approximately 20%). Consequently, elderly subjects utilised a greater percentage of their passive ankle ROM compared to the young (elderly approximately 200%; young approximately 125%). We conclude that the elderly maintained a 'foot flat' position for a longer period possibly to increase the time spent on a larger base of support. These results suggest that exercise prescription in the elderly should include stretching in order to increase the ROM at the ankle joint.


Expansion of the dehydrin gene family in the Pinaceae is associated with considerable structural diversity and drought-responsive expression.
Temperatures are expected to increase over the next century in all terrestrial biomes and particularly in boreal forests, where drought-induced mortality has been predicted to rise. Genomics research is helping to develop hypotheses regarding the molecular basis of drought tolerance and recent work proposed that the osmo-protecting dehydrin proteins have undergone a clade-specific expansion in the Pinaceae, a major group of conifer trees. The objectives of this study were to identify all of the putative members of the gene family, trace their evolutionary origin, examine their structural diversity and test for drought-responsive expression. We identified 41 complete dehydrin coding sequences in Picea glauca, which is four times more than most angiosperms studied to date, and more than in pines. Phylogenetic reconstructions indicated that the family has undergone an expansion in conifers, with parallel evolution implicating the sporadic resurgence of certain amino acid sequence motifs, and a major duplication giving rise to a clade specific to the Pinaceae. A variety of plant dehydrin structures were identified with variable numbers of the A-, E-, S- and K-segments and an N-terminal (N1) amino acid motif including assemblages specific to conifers. The expression of several of the spruce dehydrins was tissue preferential under non-stressful conditions or responded to water stress after 7-18 days without watering, reflecting changes in osmotic potential. We found that dehydrins with N1 K2 and N1 AESK2 sequences were the most responsive to the lack of water. Together, the family expansion, drought-responsive expression and structural diversification involving loss and gain of amino acid motifs suggests that subfunctionalization has driven the diversification seen among dehydrin gene duplicates. Our findings clearly indicate that dehydrins represent a large family of candidate genes for drought tolerance in spruces and in other Pinaceae that may underpin adaptability in spatially and temporally variable environments.


Analysis of Radiation Damage in Light Water Reactors: Comparison of Cluster Analysis Methods for the Analysis of Atom Probe Data.
Irradiation of reactor pressure vessel (RPV) steels causes the formation of nanoscale microstructural features (termed radiation damage), which affect the mechanical properties of the vessel. A key tool for characterizing these nanoscale features is atom probe tomography (APT), due to its high spatial resolution and the ability to identify different chemical species in three dimensions. Microstructural observations using APT can underpin development of a mechanistic understanding of defect formation. However, with atom probe analyses there are currently multiple methods for analyzing the data. This can result in inconsistencies between results obtained from different researchers and unnecessary scatter when combining data from multiple sources. This makes interpretation of results more complex and calibration of radiation damage models challenging. In this work simulations of a range of different microstructures are used to directly compare different cluster analysis algorithms and identify their strengths and weaknesses.


Defining forgiveness: christian clergy and general population perspectives.
The lack of any consensual definition of forgiveness is a serious weakness in the research literature (McCullough, Pargament, & Thoresen, 2000). As forgiveness is at the core of Christianity, this study returns to the Christian source of the concept to explore the meaning of forgiveness for practicing Christian clergy. Comparisons are made with a general population sample and social science definitions of forgiveness to ensure that a shared meaning of forgiveness is articulated. Anglican and Roman Catholic clergy (N = 209) and a general population sample (N = 159) completed a postal questionnaire about forgiveness. There was agreement on the existence of individual differences in forgiveness. Clergy and the general population perceived reconciliation as necessary for forgiveness while there was no consensus within psychology. The clergy suggest that forgiveness is limitless and that repentance is unnecessary, while the general population suggests that there are limits and that repentance is necessary. Psychological definitions do not conceptualize repentance as necessary for forgiveness, and the question of limits has not been addressed, although, within therapy, the implicit assumption is that forgiveness is limitless.


[3D ultrasound guidance for prostate biopsy with MRI-image fusion].
Endorectal prostate biopsies by using 2D ultrasound guidance remain the gold standard for diagnosing prostate cancer. However this technique is limited by a low yield knowing that only 20-30% of all prostate biopsies detect prostate cancer. Since a few years it is possible to do these biopsies by using 3D endorectal ultrasound guidance with fusion to MRI images in order to increase the yield. This new technique permits to visualize the exact localization of all biopsies and gives the certitude of a good mapping of the prostate tissue increasing the yield up to 40%. By fusioning images of the MRI with the 3D ultrasound, it is even possible to target suspect lesions visualized on the MRI, which permits to increase the yield up to 100% in favorable cases.


Establishment, Hybridization, Dispersal, Impact, and Decline of Diorhabda spp. (Coleoptera: Chrysomelidae) Released for Biological Control of Tamarisk in Texas and New Mexico.
Three Diorhabda spp. tamarisk beetles (Coleoptera: Chrysomelidae) were established in Texas from 2003 to 2010 for biological control of tamarisk (Tamarix spp.): Mediterranean tamarisk beetles, D. elongata (Brullé) from Greece, also established in New Mexico; subtropical tamarisk beetles, D. sublineata (Lucas) from Tunisia; and larger tamarisk beetles, D. carinata (Faldermann) from Uzbekistan. More than one million tamarisk beetles were released at 99 sites. Species establishment success ranged from 52 to 83%. All three species now co-occur in New Mexico with the northern tamarisk beetles, D. carinulata (Desbrochers). A phenotypic hybrid scoring system was developed to assess Diorhabda phenotype distributions and character mixing in hybrid zones. Widespread field populations of bispecific hybrid phenotypes for D. carinata/D. elongata and D. sublineata/D. elongata rapidly appeared following contact of parental species. Initial distributions and dispersal of Diorhabda spp. and hybrids are mapped for Texas, New Mexico, Oklahoma, and Kansas, where they produced large-scale tamarisk defoliation and localized dieback for 3-4 yr. However, populations subsequently severely declined, now producing only isolated defoliation and allowing tamarisk to recover. Diorhabda sublineata and D. elongata temporarily produced nontarget spillover defoliation of ornamental athel, Tamarix aphylla (L.) Karst, along the Rio Grande. Hybrid phenotypes were generally bimodally distributed, indicating some degree of reproductive isolation. Additional diagnostic phenotypic characters in males allowed more precise hybrid scoring. Character mixing in some hybrid populations approached or reached that of a hybrid swarm. The significance of hybridization for tamarisk biocontrol is discussed.


AI-3 synthesis is not dependent on luxS in Escherichia coli.
The quorum-sensing (QS) signal autoinducer-2 (AI-2) has been proposed to promote interspecies signaling in a broad range of bacterial species. AI-2 is spontaneously derived from 4,5-dihydroxy-2,3-pentanedione that, along with homocysteine, is produced by cleavage of S-adenosylhomocysteine (SAH) and S-ribosylhomocysteine by the Pfs and LuxS enzymes. Numerous phenotypes have been attributed to AI-2 QS signaling using luxS mutants. We have previously reported that the luxS mutation also affects the synthesis of the AI-3 autoinducer that activates enterohemorrhagic Escherichia coli virulence genes. Here we show that several species of bacteria synthesize AI-3, suggesting a possible role in interspecies bacterial communication. The luxS mutation leaves the cell with only one pathway, involving oxaloacetate and l-glutamate, for de novo synthesis of homocysteine. The exclusive use of this pathway for homocysteine production appears to alter metabolism in the luxS mutant, leading to decreased levels of AI-3. The addition of aspartate and expression of an aromatic amino acid transporter, as well as a tyrosine-specific transporter, restored AI-3-dependent phenotypes in an luxS mutant. The defect in AI-3 production, but not in AI-2 production, in the luxS mutant was restored by expressing the Pseudomonas aeruginosa S-adenosylhomocysteine hydrolase that synthesizes homocysteine directly from SAH. Furthermore, phenotype microarrays revealed that the luxS mutation caused numerous metabolic deficiencies, while AI-3 signaling had little effect on metabolism. This study examines how AI-3 production is affected by the luxS mutation and explores the roles of the LuxS/AI-2 system in metabolism and QS.


Psychogenic tremor: long-term prognosis in patients with electrophysiologically confirmed disease.
We describe the presenting features and long-term outcomes of patients with electrophysiologically-confirmed psychogenic tremor. Clinical information for all patients with psychogenic tremor confirmed by our Movement Disorders Neurophysiology Laboratory (2003-2004) was reviewed. A follow-up questionnaire was administered to all included patients in 2007. Psychogenic tremor was documented in 62 patients; 33 responded to the questionnaire (53%). Median onset-age was 50 years (range, 15-71); 23 were female (70%). Clinical certainty of psychogenic etiology was: definite, 8 (24%); probable, 16 (49%), and possible, 9 (27%). Characteristic electrodiagnostic features of psychogenic tremor were documented in all. All but two patients were ultimately given a definite diagnosis of psychogenic tremor; recommended psychiatric consultation was only done by 12 (36%). Twenty-one patients (64%) rated tremor disability as moderate or severe after a median follow-up of 5.1 years (range, 3.3-19). Improvement occurred spontaneously in 5 (15%), and after a specific intervention in 4 (12%), whereas 3 (9%) had mild but unchanged symptoms. The mean duration of symptoms, prior to diagnosis with psychogenic tremor, was significantly shorter for patients with mild or no tremor at follow-up (P = 0.037). Physiologically-confirmed psychogenic tremor carries a poor prognosis, with unremitting or worse tremor persisting 3-years after diagnosis in most.


Polarization of Valpha24+ Vbeta11+ natural killer T cells of healthy volunteers and cancer patients using alpha-galactosylceramide-loaded and environmentally instructed dendritic cells.
CD1d-restricted natural killer T (NKT) cells play important regulatory roles in various immune responses. NKT cell-derived T helper (Th) 1 cytokines are important in the induction of antitumor immune responses in mice. Because the CD1d-restricted Valpha24(+) Vbeta11(+) NKT cell population in cancer patients is decreased both in size and in its capacity to secrete IFN-gamma, therapeutic strategies based on reconstitution of type 1 polarized Valpha24(+) Vbeta11(+) NKT cells merit additional investigation. Here, we report the simultaneous strong expansion and type 1 polarization of human invariant Valpha24(+) Vbeta11(+) NKT cells using alpha-galactosylceramide-loaded type 1 dendritic cells and interleukin 15. Type 1 polarized Valpha24(+) Vbeta11(+) NKT cells produced high levels of IFN-gamma, tumor necrosis factor alpha, and granulocyte macrophage colony-stimulating factor, and induced strong cytotoxicity in Jurkat cells in an alpha-galactosylceramide-dependent manner. Importantly, the cytokine profile of Valpha24(+) Vbeta11(+) NKT cells that were initially expanded under Th2 polarizing conditions could be reversed to a Th1 cytokine profile, indicating the plasticity of the cytokine profile of the human adult Valpha24(+) Vbeta11(+) NKT cell population.


Counter-antigen presentation: fibroblasts produce cytokines by signalling through HLA class II molecules without inducing T-cell proliferation.
Fibroblasts are known to express histocompatibility leukocyte antigen DR (HLA-DR) molecules on their cell surface upon stimulation with interferon gamma (IFN- gamma), while the exact roles of HLA-DR on fibroblasts remain undetermined. To understand the role of HLA-DR molecules on fibroblasts, we examined whether: (1) fibroblasts act as antigen presenting cells (APC) which activate helper T (Th) cells; and/or (2) fibroblasts are activated via HLA-II molecules by making a T-cell receptor (TCR)-peptide-major histocompatibility complex (MHC) complex. We used Th(0) clone HT8.3, which recognizes an antigenic peptide (Ag53 p141-161) in the context of DRB1*1501, as well as IFN - gamma - treated and irradiated periodontal ligament fibroblasts (PDL) expressing DRB1*1501 molecules. When peptide-pulsed fibroblasts were co-incubated with HT8.3 treated by the protein synthesis inhibitor emetine, peptide-induced de novo expression of lymphokines and cell-surface molecules on T cells can be neglected. The antigen presenting capacity of these fibroblasts was evaluated by examining the proliferative responses of Th cells. Possible activation of fibroblasts by stimulation via HLA-DR molecules was evaluated by quantitating secreted cytokines in the supernatants after 18-h culture with or without anti-HLA-DR monoclonal antibody (mAb) or emetine-treated HT8.3. Indeed, Th cells did not show proliferative responses when peptide-pulsed PDL were used as APC, whereas PDL produced larger amounts of interleukin (IL) 6, IL-8, monocyte chemoattractant protein 1 (MCP-1) and regulated upon activation, normal T expressed and secreted (RANTES) compared with controls, when cultured with anti-HLA-DR mAb or emetine-treated HT8.3. These findings suggest that HLA-DR expressed on fibroblasts do not present antigens to induce T-cell proliferation, but may act as receptor molecules that transmit signals into fibroblasts, based on DR-peptide-TCR interaction, resulting in the secretion of several cytokine species.


Evaluation of techniques to model bend loss in multimode fibers for endoscopic application.
Bend loss from optical fibers can have positive applications, which need to be characterized and related to fiber curvature in a systematic approach to be useful. One potential application for optical fibers is a shape sensor for tracking flexible bodies in remote access environments, such as in endoscopy or boroscopy. We conducted a review of bend-loss characterization and evaluated several methods for characterizing bend loss in multimode optical fibers for an endoscopic shape-tracking application. Specifically, closed-form equation-based methods and numerical simulations were examined. Beam propagation method (BPM) simulations were determined to be the most applicable characterization tool. Results from simulations using BPM software were compared to experimentally obtained data. BPM simulation was sufficiently accurate for modeling 50 mum fibers but impractical for larger, multimode fibers.


Transferrin therapy ameliorates disease in beta-thalassemic mice.
Individuals with beta-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in beta-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbb(th1/th1) mice, an experimental model of beta-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human beta-thalassemia.


Modulation of Immune Responses to Herpes Simplex Virus Type 1 by IFNL3 and IRF7 Polymorphisms: A Study in Alzheimer's Disease.
Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer's disease (AD), the most common form of dementia. IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis.