Gut microbial metabolites alter IgA immunity in type 1 diabetes.
The incidence of type 1 diabetes (T1D) has been increasing among children and adolescents, in which environmental factors, including gut microbiota, play an important role. However, the underlying mechanisms are yet to be determined. Here, we show that patients with newly diagnosed T1D displayed not only a distinct profile of gut microbiota associated with decreased short-chain fatty acids (SCFAs) production, but also an altered IgA-mediated immunity compared with healthy control subjects. Using germ-free NOD mice, we demonstrate that gut microbiota from patients with T1D promoted different IgA-mediated immune responses compared with healthy control gut microbiota. Treatment with the SCFA, acetate, reduced gut bacteria-induced IgA response accompanied by decreased severity of insulitis in NOD mice. We believe our study provides new insights into the functional effects of gut microbiota on inducing IgA immune response in T1D, suggesting that SCFAs might be potential therapeutic agents in T1D prevention and/or treatment.


Unique transcriptional profile of sustained ligand-activated preconditioning in pre- and post-ischemic myocardium.
Opioidergic SLP (sustained ligand-activated preconditioning) induced by 3-5 days of opioid receptor (OR) agonism induces persistent protection against ischemia-reperfusion (I-R) injury in young and aged hearts, and is mechanistically distinct from conventional preconditioning responses. We thus applied unbiased gene-array interrogation to identify molecular effects of SLP in pre- and post-ischemic myocardium. Male C57Bl/6 mice were implanted with 75 mg morphine or placebo pellets for 5 days. Resultant SLP did not modify cardiac function, and markedly reduced dysfunction and injury in perfused hearts subjected to 25 min ischemia/45 min reperfusion. Microarray analysis identified 14 up- and 86 down-regulated genes in normoxic hearts from SLP mice (≥1.3-fold change, FDR≤5%). Induced genes encoded sarcomeric/contractile proteins (Myh7, Mybpc3,Myom2,Des), natriuretic peptides (Nppa,Nppb) and stress-signaling elements (Csda,Ptgds). Highly repressed genes primarily encoded chemokines (Ccl2,Ccl4,Ccl7,Ccl9,Ccl13,Ccl3l3,Cxcl3), cytokines (Il1b,Il6,Tnf) and other proteins involved in inflammation/immunity (C3,Cd74,Cd83, Cd86,Hla-dbq1,Hla-drb1,Saa1,Selp,Serpina3), together with endoplasmic stress proteins (known: Dnajb1,Herpud1,Socs3; putative: Il6, Gadd45g,Rcan1) and transcriptional controllers (Egr2,Egr3, Fos,Hmox1,Nfkbid). Biological themes modified thus related to inflammation/immunity, together with cellular/cardiovascular movement and development. SLP also modified the transcriptional response to I-R (46 genes uniquely altered post-ischemia), which may influence later infarction/remodeling. This included up-regulated determinants of cellular resistance to oxidant (Mgst3,Gstm1,Gstm2) and other forms of stress (Xirp1,Ankrd1,Clu), and repression of stress-response genes (Hspa1a,Hspd1,Hsp90aa,Hsph1,Serpinh1) and Txnip. Protection via SLP is associated with transcriptional repression of inflammation/immunity, up-regulation of sarcomeric elements and natriuretic peptides, and modulation of cell stress, growth and development, while conventional protective molecules are unaltered.


ClpB is the Escherichia coli heat shock protein F84.1.
ClpB is thought to be involved in proteolysis because of its sequence similarity to the ClpA subunit of the ClpA-ClpP protease. It has recently been shown that ClpP is a heat shock protein. Here we show that ClpB is the Escherichia coli heat shock protein F84.1. The F84.1 protein was overproduced in strains containing the clpB gene on a plasmid and was absent from two-dimensional gels from a clpB null mutation. Besides possessing a slower growth rate at 44 degrees C, the null mutant strain had a higher rate of death at 50 degrees C. We used reverse transcription of in vivo mRNA to show that the clpB gene was expressed from a sigma 32-specific promoter consensus sequence at both 37 and 42 degrees C. We noted that the clpB+ gene also caused the appearance of a second protein spot, F68.5, on two-dimensional gels. This spot was approximately 147 amino acids smaller than F84.1 and most probably is the result of a second translational start on the clpB mRNA. F68.5 can be observed on many published two-dimensional gels of heat-induced E. coli proteins, but the original catalog of 17 heat shock proteins did not include this spot.


Symmetrical drug-related intertriginous and flexural exanthema due to clindamycin.
Systemic drug exposure can produce a skin reaction consisting of symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) occurs after systemic exposure to a drug in which the patient was not previously sensitised, either in the first dose or after several doses. The mechanism of SDRIFE is unknown but is hypothesised to be the result of a delayed hypersensitivity response resulting in a cutaneous eruption some days after the exposure to the drug. The diagnosis should be clinical, based on the history and examination, but skin tests can also be performed to confirm sensitisation. But, as always, the gold-standard test is oral provocation. It is important to know this clinical entity to prevent re-exposure to the responsible allergen in the future.


The potential role of dietary xanthophylls in cataract and age-related macular degeneration.
The carotenoid xanthophylls, lutein and zeaxanthin, accumulate in the eye lens and macular region of the retina. Lutein and zeaxanthin concentrations in the macula are greater than those found in plasma and other tissues. A relationship between macular pigment optical density, a marker of lutein and zeaxanthin concentration in the macula, and lens optical density, an antecedent of cataractous changes, has been suggested. The xanthophylls may act to protect the eye from ultraviolet phototoxicity via quenching reactive oxygen species and/or other mechanisms. Some observational studies have shown that generous intakes of lutein and zeaxanthin, particularly from certain xanthophyll-rich foods like spinach, broccoli and eggs, are associated with a significant reduction in the risk for cataract (up to 20%) and for age-related macular degeneration (up to 40%). While the pathophysiology of cataract and age-related macular degeneration is complex and contains both environmental and genetic components, research studies suggest dietary factors including antioxidant vitamins and xanthophylls may contribute to a reduction in the risk of these degenerative eye diseases. Further research is necessary to confirm these observations.


Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER+ Breast Cancer.
Purpose:FGFR1 amplification occurs in approximately 15% of estrogen receptor-positive (ER+) human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER+/FGFR1-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR.Results: ER+/FGFR1-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER+/FGFR1-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from FGFR1-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone.Conclusions: These data suggest the ERα pathway remains active in estrogen-deprived ER+/FGFR1-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists. Clin Cancer Res; 23(20); 6138-50. ©2017 AACR.


Crystalline phases involved in the hydration of calcium silicate-based cements: Semi-quantitative Rietveld X-ray diffraction analysis.
Chemical comparisons of powder and hydrated forms of calcium silicate cements (CSCs) and calculation of alterations in tricalcium silicate (Ca3 SiO5 ) calcium hydroxide (Ca(OH)2 ) are essential for understanding their hydration processes. This study aimed to evaluate and compare these changes in ProRoot MTA, Biodentine and CEM cement. Powder and hydrated forms of tooth coloured ProRoot MTA, Biodentine and CEM cement were subjected to X-ray diffraction (XRD) analysis with Rietveld refinement to semi-quantitatively identify and quantify the main phases involved in their hydration process. Data were reported descriptively. Reduction in Ca3 SiO5 and formation of Ca(OH)2 were seen after the hydration of ProRoot MTA and Biodentine; however, in the case of CEM cement, no reduction of Ca3 SiO5 and no formation of Ca(OH)2 were detected. The highest percentages of amorphous phases were seen in Biodentine samples. Ettringite was detected in the hydrated forms of ProRoot MTA and CEM cement but not in Biodentine.


Continuum of care for maternal, newborn, and child health: from slogan to service delivery.
The continuum of care has become a rallying call to reduce the yearly toll of half a million maternal deaths, 4 million neonatal deaths, and 6 million child deaths. The continuum for maternal, newborn, and child health usually refers to continuity of individual care. Continuity of care is necessary throughout the lifecycle (adolescence, pregnancy, childbirth, the postnatal period, and childhood) and also between places of caregiving (including households and communities, outpatient and outreach services, and clinical-care settings). We define a population-level or public-health framework based on integrated service delivery throughout the lifecycle, and propose eight packages to promote health for mothers, babies, and children. These packages can be used to deliver more than 190 separate interventions, which would be difficult to scale up one by one. The packages encompass three which are delivered through clinical care (reproductive health, obstetric care, and care of sick newborn babies and children); four through outpatient and outreach services (reproductive health, antenatal care, postnatal care and child health services); and one through integrated family and community care throughout the lifecycle. Mothers and babies are at high risk in the first days after birth, and the lack of a defined postnatal care package is an important gap, which also contributes to discontinuity between maternal and child health programmes. Similarly, because the family and community package tends not to be regarded as part of the health system, few countries have made systematic efforts to scale it up or integrate it with other levels of care. Building the continuum of care for maternal, newborn, and child health with these packages will need effectiveness trials in various settings; policy support for integration; investment to strengthen health systems; and results-based operational management, especially at district level.


Factors correlated with residents' decisions to enter academic dermatology.
The demand for dermatologic services and training at academic medical centers has outpaced the growth in the field's academic workforce. Recruitment of graduating residents has been proposed as a solution to the shortage of academic dermatologists. The purpose of this study was to further our current understanding of the factors that support the recruitment and retention of academicians. A survey questionnaire was mailed to graduates of the dermatology residency program at the University of North Carolina, and data were gathered retrospectively from participants' residency application materials. The factors from residency applications that predicted initial practice setting and the driving factors behind the choice of initial practice in academia were analyzed using generalized linear models. Of the department's 39 graduates between 2005 and 2014, 37 (95%) completed our survey. Sixteen graduates (43%) remained in academia upon completion of residency, whereas fourteen graduates (38%) are currently in academic practices. Those who had obtained a PhD before starting residency were more likely than their peers to initially accept academic positions (RR 2.73, 95% CL 1.64, 4.71, p = 0.05). However, other applicant characteristics available from residency application materials poorly predicted graduates' likelihood of remaining in academia at the time of graduation. In free-text survey responses, graduates who joined academic practices upon completion of residency were significantly more likely to cite teaching opportunities (PR 3.01, 95% CL 1.60-5.78, p = 0.05) and practice environment (PR 2.97, 95% CL 1.51-6.37, p = 0.05) as factors that had strongly influenced their initial career decisions. Because it is difficult to predict which residency applicants will ultimately pursue careers in academia, promoting the desirable aspects of the academic practice setting during residency training may be a better strategy for addressing the academic workforce shortage than the selection of residency applicants who possess specific characteristics.


An antagonist for CCR4 alleviates murine allergic rhinitis by intranasal administration.
CCR4 is highly expressed on Th2 cells. These cells play an important role in acute inflammatory responses, including those involved in allergic rhinitis. We determined whether disrupting the CCR4 ligand interaction with CCR4 antagonist could alleviate allergic rhinitis in a mouse model. BALB/c mice were sensitized with ovalbumin and alum by intraperitoneal injection and challenged with intranasally administered ovalbumin. Compound 22, which has been reported as a novel small-molecule antagonist of CCR4, was also administered intranasally. In addition, budesonide, an efficient glucocorticoid, was used as a positive control. The effects of compound 22 were quantified by multiple parameters of allergic responses in both nasal and pulmonary tissues. Compound 22 significantly improved symptoms of allergic rhinitis and suppressed levels of total IgE of serum. It dramatically reduced the levels of IL-4 in bronchoalveolar lavage fluid and also decreased the number of inflammatory cells in the fluid. The infiltration of inflammatory cells, especially eosinophils, was markedly reduced in the nasal and pulmonary tissues. The number of IL-4+ cells was also significantly reduced in these tissues. Moreover, the numbers of Foxp3+ cells and IL-17+ cells were reduced, though not to a statistically significant degree. In our research, CCR4 antagonists such as compound 22 were proven for the first time to alleviate murine allergic rhinitis when administered nasally. CCR4 antagonists may have therapeutic potential for the treatment of allergic rhinitis.


N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation.
Among human N-formyl peptide chemoattractant receptors, FPR2/ALX and FPR3 share the highest degree of amino acid identity (83%), and trigger similar cell responses upon ligand binding. Although FPR2/ALX is a promiscuous receptor, FPR3 has only one specific high affinity ligand, F2L, and a more restricted tissue/cell distribution. In this study, we showed that FPR2/ALX behaved as the prototypical receptor FPR1. The agonist-dependent phosphorylation used a hierarchical mechanism with a prominent role of Ser(329), Thr(332), and Thr(335). Phosphorylation of FPR2/ALX was essential for its desensitization but the lack of phosphorylation did not result in enhanced or sustained responses. In contrast, resting FPR3 displayed a marked level of phosphorylation, which was only slightly increased upon agonist stimulation. Another noticeable difference between the two receptors was their subcellular distribution in unstimulated cells. Although FPR2/ALX was evenly distributed at the plasma membrane FPR3 was localized in small intracellular vesicles. By swapping domains between FPR2/ALX and FPR3, we uncovered the determinants involved in the basal phosphorylation of FPR3. Experiments aimed at monitoring receptor-bound antibody uptake showed that the intracellular distribution of FPR3 resulted from a constitutive internalization that was independent of C terminus phosphorylation. Unexpectedly, exchanging residues 1 to 53, which encompass the N-terminal extracellular region and the first transmembrane domain, between FPR2/ALX and FPR3 switched localization of the receptors from the plasma membrane to intracellular vesicles and vice versa. A clathrin-independent, possibly caveolae-dependent, mechanism was involved in FPR3 constitutive internalization. The peculiar behavior of FPR3 most probably serves distinct physiological functions that remain largely unknown.


Effects of CCK-8 and GLP-1 on fatty acid sensing and food intake regulation in trout.
We hypothesize that cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) are involved in the modulation of metabolic regulation of food intake by fatty acids in fish. Therefore, we assessed in rainbow trout (Oncorhynchus mykiss) the effects of intracerebroventricular treatment with 1 ng/g of CCK-8 and with 2 ng/g of GLP-1 on food intake, expression of neuropeptides involved in food intake control and the activity of fatty acid-sensing systems in hypothalamus and hindbrain. Food intake decreased up to 24 h post-treatment to 49.8-72.3% and 3.1-17.8% for CCK-8 and GLP-1, respectively. These anorectic responses are associated with changes in fatty acid metabolism and an activation of fatty acid-sensing mechanisms in the hypothalamus and hindbrain. These changes occurred in parallel with those in the expression of anorexigenic and orexigenic peptides. Moreover, we observed that the activation of fatty acid sensing and the enhanced anorectic potential elicited by CCK-8 and GLP-1 treatments occurred in parallel with the activation of mTOR and FoxO1 and the inhibition of AMPKα, BSX and CREB. The results are discussed in the context of metabolic regulation of food intake in fish.


The relation between invasive and noninvasive tear break-up time.
TBUT and NITBUT (tear break-up time and noninvasive tear break-up time, respectively) were measured on four groups of subjects from different countries (two groups of Caucasians, two groups of Chinese). No significant difference was found in either TBUT or NITBUT values among the four groups of subjects. Gender of the subjects was not a factor affecting the TBUT or NITBUT values. The distributions of both NITBUT and TBUT were non-Gaussian and the median value of either parameter was lower than those previously reported. The NITBUT values were significantly higher than the TBUT values in both Caucasian and Chinese subjects. An investigation into the extent of agreement between the TBUT and NITBUT methods of assessing tear stability indicated that these methods do not agree sufficiently closely (that is, tear stability values measured with the NITBUT technique do not agree with those measured with the TBUT technique); short average tear break-up values are associated with small differences between the measures, whereas long average tear break-up values are associated with large differences between the measures.


Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes.
To characterize the effects of cerebrovascular (CV) risk factors on preclinical memory decline in cognitively normal individuals at 3 levels of genetic risk for Alzheimer disease (AD) based on APOE genotype. We performed longitudinal neuropsychological testing on an APOE ε4 enriched cohort, ages 21-97. The long-term memory (LTM) score of the Auditory Verbal Learning Test (AVLT) was the primary outcome measure. Any of 4 CV risk factors (CVany), including hypercholesterolemia (CHOL), prior cigarette use (CIG), diabetes mellitus (DM), and hypertension (HTN), was treated as a dichotomized variable. We estimated the longitudinal effect of age using statistical models that simultaneously modeled the cross-sectional and longitudinal effects of age on AVLT LTM by APOE genotype, CVany, and the interaction between the two. A total of 74 APOE ε4 homozygotes (HMZ), 239 ε4 heterozygotes (HTZ), and 494 ε4 noncarriers were included. APOE ε4 carrier status showed a significant quadratic effect with age-related LTM decline in all models as previously reported. CVany was associated with further longitudinal AVLT LTM decline in APOE ε4 carriers (p=0.02), but had no effect in noncarriers. When ε4 HTZ and HMZ were considered separately, there was a striking effect in HMZ (p<0.001) but not in HTZ. In exploratory analyses, significant deleterious effects were found for CIG (p=0.001), DM (p=0.03), and HTN (p=0.05) in APOE ε4 carriers only that remained significant only for CIG after correction for multiple comparisons. CV risk factors influence age-related memory decline in APOE ε4 HMZ.


Validation of a questionnaire to identify hearing loss among farm operators.
Workers in certain industries (e.g., agriculture) do not participate in a hearing conservation program and rarely receive this important preventive care. The National Institute for Deafness and Communication Disorders (NIDCD) has published a questionnaire to assess a person's need for medical examination of their hearing. The use of a self-administered questionnaire may pose a simple, low cost opportunity to assess the hearing health of workers not included in a hearing conservation program. However, the validity of the NIDCD questionnaire has not been tested. A study was conducted to compare the results of audiometric screening and the NIDCD questionnaire in identifying persons at risk for hearing impairment who may benefit from a medical referral. Data were collected from 103 farm operators at a regional farm show. Receiver-operator characteristic curves, measuring the ability of the questionnaire to correctly classify those with and without the disease suggested that the level of performance of the questionnaire as a whole, ranged from 0.74 to 0.69 (fair to poor). However, selected questionnaire items (e.g., Do you have to strain to understand conversations?) had moderate agreement (0.38 to 0.41) with screening audiogram results. Overall, the 10-item instrument did not perform as well as instruments with fewer items reported in separate studies. These findings suggest that, while less desirable than audiometry, alternative self-administered instruments might perform the better in this group. This approach may be useful as an alternative screening method to detect risk of hearing loss and identifying the need for medical evaluation of hearing sensitivity, particularly among farm operators.


Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis.
Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->6)}-beta-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 +/- 0.18 - 48.90 +/- 0.40 microM but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 +/- 1.04 and 9.32 +/- 0.082 muM respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis.


Therapeutic potential of ginseng in the management of cardiovascular disorders.
Although employed in Asian societies for thousands of years, the use of ginseng as an herbal medication for a variety of disorders has increased tremendously worldwide in recent years. Ginseng belongs to the genus Panax, of which there exists a variety, generally reflecting their geographic origin. North American ginseng (Panax quinquefolius) and Asian ginseng (Panax ginseng) are two such varieties possessing a plethora of pharmacological properties, which are attributed primarily to the presence of different ginsenosides that bestow these ginsengs with distinct pharmacodynamic profiles. The many cardiovascular benefits attributed to ginseng include cardioprotection, antihypertensive effects, and attenuation of myocardial hypertrophy and heart failure. Experimental studies have revealed a number of beneficial properties of ginseng, particularly in the area of cardiac protection, where ginseng and ginsenosides have been shown to protect the ischaemic and reperfused heart in a variety of experimental models. Emerging evidence also suggests that ginseng attenuates myocardial hypertrophy, thus blunting the remodelling and heart failure processes. However, clinical evidence of efficacy is not convincing, likely owing primarily to the paucity of well designed, randomized, controlled clinical trials. Adding to the complexity in understanding the cardiovascular effects of ginseng is the fact that each of the different ginseng varieties possesses distinct cardiovascular properties, as a result of their respective ginsenoside composition, rendering it difficult to assign a general, common cardiovascular effect to ginseng. Additional challenges include the identification of mechanisms (likely multifaceted) that account for the effects of ginseng and determining which ginsenoside(s) mediate these cardiovascular properties. These concerns notwithstanding, the potential cardiovascular benefit of ginseng is worthy of further studies in view of its possible development as a cardiovascular therapeutic agent, particularly as adjunctive therapy to existing medications.


Traumatic trabecular lesions observed on MR imaging of the knee.
Examinations carried out on 302 consecutive patients with MR of the knee between January 1988 and March 1989 were reviewed for detection of trabecular lesion. Twenty-seven patients found presenting trabecular lesion were further reviewed with specific reference to their activity level and need for specific therapy to determine the clinical significance of the trabecular lesion. Twenty-one of the trabecular lesions were in the femur, 5 were in the tibia, and one was in the fibula. Three of them were associated with a direct trauma, 12 with a valgus type injury, 3 with pure rotation mechanism, and 5 with a combination of valgus and rotation. In 17 cases trabecular lesion was a single finding, in 10 cases it was associated with some ligamentous tear. At the follow-up visit, 26 of the 27 patients with trabecular lesion had no symptoms, and the patient with moderate knee symptoms had had similar knee symptoms prior to the accident due to an osteochondral defect. We conclude that a trabecular lesion in an MR image is a benign bone change associated with knee trauma which heals without sequelae.


[The patient with chronic low back pain in a thermal spa].
We have made our study over a period of five months. Out of 553 patients admitted to the Thermal Clinic at Lavey-les-Bains, we observed 111 patients suffering from chronic low-back pain, noting the changes, both subjective and objective, during their three-week stay at the clinic. From the physical aspect, they were encouraged to increase lumbothoracic mobility. From the subjective aspect, an evaluation of pain and handicap level, was made using a visual comparison scale and the completion of a questionnaire. We concluded that, in the short term, thermal treatment resulted in an appreciable relief of pain for these patients. In the long term, however, in view of the changing developments in clinical measuring techniques it is not possible to estimate in advance the functional effectiveness of treatment.


HOX4 genes encode transcription factors with potential auto- and cross-regulatory capacities.
We have looked for the binding of several HOX4 complex homeoproteins in the genomic region containing the HOX4C promoter, between the human HOX4C and HOX4D genes. The HOX4C, HOX4D and Hox-4.3 homeoproteins bind to a phylogenetically highly conserved DNA fragment, which is located in the proximal part of this intergenic region and contains multiple binding sites for these HOX4 proteins. Using cotransfection experiments, we show that this endogenous DNA sequence can mediate transactivation by the HOX4D and HOX4C proteins and that this effect requires the presence of TAAT-related binding sites. The Hox-4.3 protein, in contrast, is unable to activate and can repress the activation observed with the two other proteins. These results show that the HOX4D and HOX4C genes are genuine sequence-specific transcription factors and suggest that, as in Drosophila, cross-regulatory interactions between these genes might be essential for their proper expression.


Health literacy: what is it and why is it important to measure?
This report summarizes the proceedings of the first Outcome Measures in Rheumatology Clinical Trials (OMERACT) Health Literacy Special Interest Group workshop at the OMERACT 10 conference. Health literacy refers to an individual's capacity to seek, understand, and use health information. Discussion centered on the relevance of health literacy to the rheumatology field; whether measures of health literacy were important in the context of clinical trials and routine care; and, if so, whether disease-specific measures were required. A nominal group process involving 27 workshop participants, comprising a patient group (n = 12) and a healthcare professional and researcher group (n = 15), confirmed that health literacy encompasses a broad range of concepts and skills that existing scales do not measure. It identified the importance and relevance of patient abilities and characteristics, but also health professional factors and broader contextual factors. Sixteen themes were identified: access to information; cognitive capacity; disease; expression/communication; finances; health professionals; health system; information; literacy/numeracy; management skills; medication; patient approach; dealing with problems; psychological characteristics; social supports; and time. Each of these was divided further into subthemes of one or more of the following: knowledge, attitude, attribute, relationship, skill, action, or context. There were virtually no musculoskeletal-specific statements, suggesting that a generic health literacy tool in rheumatology is justified. The detailed concepts across themes provided new and systematic insight into what needs to be done to improve health literacy and consequently reduce health inequalities. These data will be used to derive a more comprehensive measure of health literacy.


Subcellular interactions of dietary cadmium, copper and zinc in rainbow trout (Oncorhynchus mykiss).
Interactions of Cu, Cd and Zn were studied at the subcellular level in juvenile rainbow trout (Oncorhynchus mykiss) fed diets containing (μg/g) 500 Cu, 1000 Zn and 500 Cd singly and as a ternary mixture for 28 days. Livers were harvested and submitted to differential centrifugation to isolate components of metabolically active metal pool (MAP: heat-denaturable proteins (HDP), organelles, nuclei) and metabolically detoxified metal pool (MDP: heat stable proteins (HSP), NaOH-resistant granules). Results indicated that Cd accumulation was enhanced in all the subcellular compartments, albeit at different time points, in fish exposed to the metals mixture relative to those exposed to Cd alone, whereas Cu alone exposure increased Cd partitioning. Exposure to the metals mixture reduced (HDP) and enhanced (HSP, nuclei and granules) Cu accumulation while exposure to Zn alone enhanced Cu concentration in all the fractions analyzed without altering proportional distribution in MAP and MDP. Although subcellular Zn accumulation was less pronounced than that of either Cu or Cd, concentrations of Zn were enhanced in HDP, nuclei and granules from fish exposed to the metals mixture relative to those exposed to Zn alone. Cadmium alone exposure mobilized Zn and Cu from the nuclei and increased Zn accumulation in organelles and Cu in granules, while Cu alone exposure stimulated Zn accumulation in HSP, HDP and organelles. Interestingly, Cd alone exposure increased the partitioning of the three metals in MDP indicative of enhanced detoxification. Generally the accumulated metals were predominantly metabolically active: Cd, 67-83%; Cu, 68-79% and Zn, 60-76%. Taken together these results show both competitive and cooperative interactions dependent on the subcellular fraction, metal, exposure duration and relative metal exposure concentrations. Competitive interactions likely result from ionic mimicry with the metals displacing each other from common binding sites, whereas cooperative interactions suggest increased abundance of metal binding sites and/or existence of metal-specific non-interacting binding sites in some of the fractions. Moreover, the changes in subcellular distribution of the biometals Cu and Zn due to Cd exposure together with the shifts of the metals between MAP and MDP observed may have toxicological consequences.


Get the right mix of bricks & clicks.
The bright line that once distinguished the dot-com from the incumbent is rapidly fading. Success in the new economy will go to those who can execute clicks-and-mortar strategies that bridge the physical and virtual worlds. But how executives forge such strategies is under considerable debate. Despite the obvious benefits that integration offers--cross-promotion, shared information, purchasing leverage, distribution economies, and the like--many executives now assume that Internet businesses have to be separate to thrive. They believe that the very nature of traditional business--its protectiveness of current customers, its fear of cannibalization, its general myopia--will smother any Internet initiative. Authors Ranjay Gulati and Jason Garino contend that executives don't have to make an either- or choice when it comes to their clicks-and-mortar strategies. The question isn't, "Should we develop our Internet channel in-house or launch a spin-off?" but rather, "What degree of integration makes sense for our company?" To determine the best level of integration for their companies, executives should examine four business dimensions: brand, management, operations, and equity. Drawing on the experiences of three established retailers--Office Depot, KB Toys, and Rite Aid--the authors show the spectrum of strategies available and discuss the trade-offs involved in each choice. By thinking carefully about which aspects of a business to integrate and which to keep distinct, companies can tailor their clicks-and-mortar strategy to their own particular market and competitive situation, dramatically increasing their odds of e-business success.


Data mining the p53 pathway in the Fugu genome: evidence for strong conservation of the apoptotic pathway.
The p53 tumour suppressor gene belongs to a small family of related proteins that includes two other members, p63 and p73. Phylogenetic and functional studies suggest that p63 and p73 are ancient genes that have essential roles in normal development, whereas p53 seems to have evolved more recently to prevent cell transformation. In mammalian cells, a plethora of proteins have been found to specifically regulate p53 activity. The genome of the fish Fugu rubripes has been recently published. It is the second vertebrate genome for which the entire sequence is now available. Phylogenetic studies are essential in order to analyse and define signalling pathways important for cell cycle regulation. The presence or absence of a critical member in any pathway can shed light about the evolution of these pathways. The Fugu genome databank has been analysed for several members of the p53 network, including p53, p63 and p73. A good conservation of the network that regulates p53 stability and apoptosis has been found. We also discovered that some cofactors that cooperate with p53 for apoptosis are also well conserved and belong to multigene families not detected in the human genome.


Influence of indoor factors in dwellings on the development of childhood asthma.
Asthma has become the most common, childhood chronic disease in the industrialized world, and it is also increasing in developing regions. There are huge differences in the prevalence of childhood asthma across countries and continents, and there is no doubt that the prevalence of asthma was strongly increasing during the past decades worldwide. Asthma, as a complex disease, has a broad spectrum of potential determinants ranging from genetics to life style and environmental factors. Environmental factors are likely to be important in explaining the regional differences and the overall increasing trend towards asthma's prevalence. Among the environmental conditions, indoor factors are of particular interest because people spend more than 80% of their time indoors globally. Increasing prices for oil, gas and other sources of primary energy will further lead to better insulation of homes, and ultimately to reduced energy costs. This will decrease air exchange rates and will lower the dilution of indoor air mass with ambient air. Indoor air quality and potential health effects will therefore be an area for future research and for gaining a better understanding of asthma epidemics. This strategic review will summarize the current knowledge of the effects of a broad spectrum of indoor factors on the development of asthma in childhood in Western countries based on epidemiological studies. In conclusion, several epidemiological studies point out, that indoor factors might cause asthma in childhood. Stronger and more consistent findings are seen when exposure to these indoor factors is assessed by surrogates for the source of the actual toxicants. Measurement-based exposure assessments for several indoor factors are less common than using surrogates of the exposure. These studies, however, mainly showed heterogeneous results. The most consistent finding for an induction of asthma in childhood is related to exposure to environmental tobacco smoke, to living in homes close to busy roads, and in damp homes where are visible moulds at home. The causing agents of the increased risk of living in damp homes remained uncertain and needs clarification. Exposure to pet-derived allergens and house dust mites are very commonly investigated and thought to be related to asthma onset. The epidemiological evidence is not sufficient to recommend avoidance measures against pet and dust mites as preventive activities against allergies. More research is also needed to clarify the potential risk for exposure to volatile and semi-volatile organic compounds due to renovation activities, phthalates and chlorine chemicals due to cleaning.


Seeds of change: corn seed mixtures for resistance management and integrated pest management.
The use of mixtures of transgenic insecticidal seed and nontransgenic seed to provide an in-field refuge for susceptible insects in insect-resistance-management (IRM) plans has been considered for at least two decades. However, the U.S. Environmental Protection Agency has only recently authorized the practice. This commentary explores issues that regulators, industry, and other stakeholders should consider as the use of biotechnology increases and seed mixtures are implemented as a major tactic for IRM. We discuss how block refuges and seed mixtures in transgenic insecticidal corn, Zea mays L., production will influence integrated pest management (IPM) and the evolution of pest resistance. We conclude that seed mixtures will make pest monitoring more difficult and that seed mixtures may make IRM riskier because of larval behavior and greater adoption of insecticidal corn. Conversely, block refuges present a different suite of risks because of adult pest behavior and the lower compliance with IRM rules expected from farmers. It is likely that secondary pests not targeted by the insecticidal corn as well as natural enemies will respond differently to block refuges and seed mixtures.


Oxidative DNA damage and repair in skeletal muscle of humans exposed to high-altitude hypoxia.
Recent research suggests that high-altitude hypoxia may serve as a model for prolonged oxidative stress in healthy humans. In this study, we investigated the consequences of prolonged high-altitude hypoxia on the basal level of oxidative damage to nuclear DNA in muscle cells, a major oxygen-consuming tissue. Muscle biopsies from seven healthy humans were obtained at sea level and after 2 and 8 weeks of hypoxia at 4100 m.a.s.l. We found increased levels of strand breaks and endonuclease III-sensitive sites after 2 weeks of hypoxia, whereas oxidative DNA damage detected by formamidopyrimidine DNA glycosylase (FPG) protein was unaltered. The expression of 8-oxoguanine DNA glycosylase 1 (OGG1), determined by quantitative RT-PCR of mRNA levels did not significantly change during high-altitude hypoxia, although the data could not exclude a minor upregulation. The expression of heme oxygenase-1 (HO-1) was unaltered by prolonged hypoxia, in accordance with the notion that HO-1 is an acute stress response protein. In conclusion, our data indicate high-altitude hypoxia may serve as a good model for oxidative stress and that antioxidant genes are not upregulated in muscle tissue by prolonged hypoxia despite increased generation of oxidative DNA damage.


Evaluation of mild lameness in horses trotting on a treadmill by clinicians and interns or residents and correlation of their assessments with kinematic gait analysis.
To estimate sensitivity and accuracy of subjective evaluation of mild lameness in horses during treadmill locomotion and to correlate subjective evaluation with kinematic analysis. 19 lame and 5 clinically normal horses. Lameness was evaluated by subjective score and kinematic analysis before and after palmar digital nerve block (PDNB). Evaluations were made by 6 clinicians and 7 interns or residents. Within- and between-observer agreement analyses (kappa values) were calculated and compared, using a Student's t-test. Pearson's product-moment correlation coefficients were calculated between clinician's change in score and the change in kinematic variables after PDNB. Within-observer agreement was within the range expected for conditions of moderate diagnostic difficulty. Within-observer agreement was higher for clinicians than for interns or residents. Between-observer agreement was acceptable for scores within 1 value of each other. Between-observer agreement of change in lameness score after PDNB was poor. When kinematic variables were ranked with each clinician's subjective change in score, only 2 were among the top 3 for the majority of clinicians. Asymmetry of vertical head movement between contralateral forelimb stance phases and the point of maximum hoof height during swing decreased as lameness subjectively improved. Mild lameness may be difficult to evaluate during treadmill locomotion. Although clinicians were more repeatable in their subjective evaluation of lameness than interns or residents, they were not more reliable at detecting the true state of lameness. Lack of agreement between clinician scoring of mild lameness emphasizes the need to use more objective measures for quantifying lameness.


Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy.
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, raising hopes for many patients with otherwise unresponsive tumours. While these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. Many of these toxic effects result from downstream inhibition of vascular endothelial growth factor or epidermal growth factor signalling in cells of normal organs. Many of these undesirable effects such as hypertension, hypothyroidism, skin reactions and possibly proteinuria are on-target effects. Since tyrosine kinases are widely distributed with specific functional roles in different organs, this association is not too surprising. Various studies suggest that the development of these on-target effects indicates clinically desirable and effective inhibition of the corresponding ligand-mediated receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target adverse effects compared with those who do not. Inevitably, issues arise with respect to the regulatory assessment of efficacy and risk/benefit of the TKIs as well as the clinical approach to managing patients who develop these effects. Routine subgroup analysis of efficacy data from clinical trials (patients with and without on-target toxicity) may enable more effective clinical use of TKIs since (i) discontinuing or reducing the dose of the TKI has a negative impact if the tumour is TKI-responsive; and (ii) it is usually possible to manage these undesirable on-target effects with conventional clinical approaches. Prospective studies are needed to investigate this proposition further.


Mechanisms of cigarette smoke induced increased airspace permeability.
Increased epithelial permeability of the airspaces occurs commonly in the lungs of cigarette smokers. It is likely to be important in augmenting the inflammatory response in the airspaces and hence may have a role in the pathogenesis of emphysema. It has previously been shown that intratracheal instillation of cigarette smoke condensate induces increased epithelial permeability in vivo in rats and in vitro in epithelial cell monolayers, associated with a disturbance in the lung antioxidant, glutathione (GSH). The aim of this study was to assess the role of neutrophils, GSH, and tumour necrosis factor (TNF) in the increased epithelial permeability following intratracheal instillation of cigarette smoke condensate. Epithelial permeability of the airspaces was measured in rat lungs as the passage of intratracheally instilled 125-iodine labelled bovine serum albumin (BSA) into the blood. The permeability of a monolayer of human type II alveolar epithelial cells to 125I-BSA was also measured. Cigarette smoke condensate produced a 59.7% increase in epithelial permeability over control values peaking six hours after instillation and returning to control values by 24 hours. Depletion of neutrophils and, to a lesser extent, macrophages by an intraperitoneal injection of antineutrophil antibody did not influence the increased epithelial permeability induced by cigarette smoke condensate. Although instillation of human recombinant TNF alpha produced an increase in epithelial permeability in the rat lung from 0.62 (0.61)% to 1.27 (0.08)%, only a trivial amount of TNF alpha was detected in bronchoalveolar lavage (BAL) fluid in vivo or in culture medium from BAL leucocytes obtained from animals treated with cigarette smoke condensate (94.9 (28.8) units/ml). Furthermore, antiTNF antibody did not abolish the increased epithelial permeability produced by cigarette smoke condensate. The role of GSH was assessed by measuring the changes in both the reduced (GSH) and oxidised form (GSSG) in lung tissue and in BAL fluid. One hour after instillation of cigarette smoke condensate there was a marked fall in the GSH content in the lung (from 809.8 (31.8) to 501.7 (40.5) nmol/g) in association with increased GSSG levels (from 89.8 (2.7) to 148.7 (48.8) nmol/g). This was followed by a return of GSH levels to control values, with a concomitant decrease in GSSG levels six hours after instillation. GSH levels in BAL fluid fell dramatically following cigarette smoke condensate (from 2.56 (0.30) to 0.31 (0.21) nmol/ml) and this fall was sustained up to six hours after instillation of cigarette smoke condensate. These studies suggest that neutrophils and TNF do not have a major role in the increased epithelial permeability induced by cigarette smoke condensate. However, the data support a role for the depletion of the antioxidant glutathione in the increased epithelial permeability caused by cigarette smoke condensate.


Synthesis and magneto-structural studies on a new family of carbonato bridged 3d-4f complexes featuring a [CoLn(CO3)] (Ln = La, Gd, Tb, Dy and Ho) core: slow magnetic relaxation displayed by the cobalt(ii)-dysprosium(iii) analogue.
A new family of [3 + 3] hexanuclear 3d-4f complexes [(μ3-CO3){CoIILnIIIL(μ3-OH)(OH2)}3]-(ClO4)·mC2H5OH·nH2O (1-5) [Ln = La (1), Gd (2), Tb (3), Dy (4), and Ho (5)] have been prepared in moderate to high yields (62-78%) following a self-assembly reaction between the ligand 6,6',6''-(nitrilotris(methylene))tris-(2-methoxy-4-methylphenol) (H3L), Co(OAc)2·4H2O and the lanthanide ion precursors in the mandatory presence of tetrabutylammonium hydroxide. During the reaction, atmospheric carbon dioxide is fixed in the product molecule as a bridging carbonato ligand which connects all the three lanthanide centers of this molecular assembly through a rare η2:η2:η2-μ3 mode of bridging as revealed from X-ray crystallography. The metal centers in all these compounds, except the GdIII analogue (2), are coupled in antiferromagnetic manner while the nature of coupling in the CoGd complex is ferromagnetic. DFT calculations revealed that this ferromagnetic interaction occurs most likely by the CoII-GdIII superexchange, mediated via the bridging oxygen atoms. Only the CoII-DyIII compound (4) displayed a slow relaxation of the magnetization at a very low temperature as established by AC susceptibility measurements. The data provides an estimation of the activation energy U/kB = 9.2 K and the relaxation time constant τ0 = 1.0 × 10-7 s.


Assessment and optimization of Theileria parva sporozoite full-length p67 antigen expression in mammalian cells.
Delivery of various forms of recombinant Theileria parva sporozoite antigen (p67) has been shown to elicit antibody responses in cattle capable of providing protection against East Coast fever, the clinical disease caused by T. parva. Previous formulations of full-length and shorter recombinant versions of p67 derived from bacteria, insect, and mammalian cell systems are expressed in non-native and highly unstable forms. The stable expression of full-length recombinant p67 in mammalian cells has never been described and has remained especially elusive. In this study, p67 was expressed in human-derived cells as a full-length, membrane-linked protein and as a secreted form by omission of the putative transmembrane domain. The recombinant protein expressed in this system yielded primarily two products based on Western immunoblot analysis, including one at the expected size of 67 kDa, and one with a higher than expected molecular weight. Through treatment with PNGase F, our data indicate that the larger product of this mammalian cell-expressed recombinant p67 cannot be attributed to glycosylation. By increasing the denaturing conditions, we determined that the larger sized mammalian cell-expressed recombinant p67 product is likely a dimeric aggregate of the protein. Both forms of this recombinant p67 reacted with a monoclonal antibody to the p67 molecule, which reacts with the native sporozoite. Additionally, through this work we developed multiple mammalian cell lines, including both human and bovine-derived cell lines, transduced by a lentiviral vector, that are constitutively able to express a stable, secreted form of p67 for use in immunization, diagnostics, or in vitro assays. The recombinant p67 developed in this system is immunogenic in goats and cattle based on ELISA and flow cytometric analysis. The development of a mammalian cell system that expresses full-length p67 in a stable form as described here is expected to optimize p67-based immunization.


Sinus Augmentation with Biomimetic Nanostructured Matrix: Tomographic, Radiological, Histological and Histomorphometrical Results after 6 Months in Humans.
Background: Many bone substitutes have been applied for sinus regeneration procedures, such as autogenous bone, inorganic bovine bone, porous and resorbable hydroxyapatite, tricalcium phosphate, bioactive glass, and blood clots. The aim of the present study was a tomographic, histological and histomorphometrical evaluation in humans, of specimens retrieved from sinuses augmented with MgHA/collagen-based scaffolds, after a healing period of 6 months. Materials and Methods: Eleven healthy patients and a total of 15 sinuses were included in this study. The maxillary sinuses were filled with commercial MgHA/collagen-based scaffolds (RegenOss) with a porous three-dimensional (3D) structure (Fin-Ceramica Faenza S.p.A., Faenza, Italy). These grafts have a composite design, that replicate the organization of bone structure, obtained by a technique in which a specific hybrid organic-inorganic composite is spontaneously built by a biological mechanism. The CBCT scans were done before the procedure, after the surgical protocol (T1), and 6 months after sinus surgery (T2) for implantology. Bone specimens were stored in 10% formalin solution, embedded in a glycolmethacrylate resin and sectioned by a high-precision diamond disc. Histologic and histomorphometric analysis were carried out to evaluate the graft reabsorption and bone healing. Results: The mean volume after graft elevation, calculated for each of the 15 sinuses, was 2,906 mm3 in the immediate postoperative period (5-7 days), ranging from 2,148.8 to 3,146.4 mm3. In the late postoperative period (6 months) it was 2,806.7 mm3, ranging from 2,010.9 to 3,008.9 mm3. The sinuses were completely healed and no residual MgHA/collagen-based scaffolds were visible. Osteoblasts appeared actively secreting bone matrix and marrow spaces contained moderate numbers of stromal cells and vascular network. Osteoblasts were observed actively secreting osteoid matrix. The tissues present in the samples were composed of 1.9 ± 1.9% of lamellar bone, 36 ± 1% of woven bone and 58 ± 3.8% of marrow spaces. Conclusion: Mg-MgHA/collagen-based scaffolds can successfully be used for sinus augmentation procedures.


The Public Stigma of Problem Gambling: Its Nature and Relative Intensity Compared to Other Health Conditions.
Problem gambling attracts considerable public stigma, with deleterious effects on mental health and use of healthcare services amongst those affected. However, no research has examined the extent of stigma towards problem gambling within the general population. This study aimed to examine the stigma-related dimensions of problem gambling as perceived by the general public compared to other health conditions, and determine whether the publicly perceived dimensions of problem gambling predict its stigmatisation. A sample of 2000 Australian adults was surveyed, weighted to be representative of the state population by gender, age and location. Based on vignettes, the online survey measured perceived origin, peril, concealability, course and disruptiveness of problem gambling and four other health conditions, and desired social distance from each. Problem gambling was perceived as caused mainly by stressful life circumstances, and highly disruptive, recoverable and noticeable, but not particularly perilous. Respondents stigmatised problem gambling more than sub-clinical distress and recreational gambling, but less than alcohol use disorder and schizophrenia. Predictors of stronger stigma towards problem gambling were perceptions it is caused by bad character, is perilous, non-recoverable, disruptive and noticeable, but not due to stressful life circumstances, genetic/inherited problem, or chemical imbalance in the brain. This new foundational knowledge can advance understanding and reduction of problem gambling stigma through countering inaccurate perceptions that problem gambling is caused by bad character, that people with gambling problems are likely to be violent to other people, and that people cannot recover from problem gambling.


Biologics for the treatment of juvenile idiopathic arthritis: a systematic review and critical analysis of the evidence.
Biologics are an important therapeutic option for treating patients with juvenile idiopathic arthritis (JIA). In adults, they are associated with rare but severe adverse events such as serious infections and malignancies. We reviewed systematically the evidence on the efficacy and safety of biologics for the treatment of JIA. We searched electronic databases up to August 2006. We limited evidence to prospective studies for efficacy but included retrospective observational evidence for safety. Outcomes of interest were clinical response, radiographic progression, quality of life, and adverse events. One randomized controlled trial (RCT) and 11 uncontrolled prospective studies provided data on efficacy; three additional studies assessed safety. The only RCT and six uncontrolled trials support the general efficacy of etanercept for the treatment of JIA. Internal and external validity of these studies are limited. The evidence on other biologic agents such as adalimumab, abatacept, anakinra, infliximab, rituximab, and tocilizumab is sparse or entirely missing. Because of the lack of sound long-term safety data, evidence is insufficient to draw firm conclusions about the balance of risks and benefits of any biologic agent for the treatment of JIA. Clinicians have to be aware of the lack of evidence supporting a long-term net benefit when considering biologics for patients with JIA.


Phylogenetic simulation of promoter evolution: estimation and modeling of binding site turnover events and assessment of their impact on alignment tools.
The phenomenon of functional site turnover has important implications for the study of regulatory region evolution, such as for promoter sequence alignments and transcription factor binding site (TFBS) identification. At present, it remains difficult to estimate TFBS turnover rates on real genomic sequences, as reliable mappings of functional sites across related species are often not available. As an alternative, we introduce a flexible new simulation system, Phylogenetic Simulation of Promoter Evolution (PSPE), designed to study functional site turnovers in regulatory sequences. Using PSPE, we study replacement turnover rates of different individual TFBSs and simple modules of two sites under neutral evolutionary functional constraints. We find that TFBS replacement turnover can happen rapidly in promoters, and turnover rates vary significantly among different TFBSs and modules. We assess the influence of different constraints such as insertion/deletion rate and translocation distances. Complementing the simulations, we give simple but effective mathematical models for TFBS turnover rate prediction. As one important application of PSPE, we also present a first systematic evaluation of multiple sequence aligners regarding their capability of detecting TFBSs in promoters with site turnovers. PSPE allows researchers for the first time to investigate TFBS replacement turnovers in promoters systematically. The assessment of alignment tools points out the limitations of current approaches to identify TFBSs in non-coding sequences, where turnover events of functional sites may happen frequently, and where we are interested in assessing the similarity on the functional level. PSPE is freely available at the authors' website.


[Acute arrest of hemopoiesis mimics aplastic anemia: 23 cases report].
To reveal the clinical features of patients with acute arrest of hemopoiesis (AAH), and explore the dissimilarity between AAH, severe aplastic anemia (SAA) and very severe aplastic anemia (vSAA). The clinical and laboratory features of 23 AAH patients diagnosed and treated in our hospital from May 1993 to May 2006 were analysed retrospectively and compared to the 111 cases of SAA and vSAA patients diagnosed at anaemia therapeutic centre of the hospital from Jul 2002 to May 2006. Twenty-three patients accorded with the criteria for AAH, and 16 of them with the criteria for severe acute arrest of hemopoiesis (SAAH). They could spontaneously reconstitute their bone marrow hematopoiesis at a median of 17 days (range, 8-50), and had remarkable older age (median age 35.5 vs 21), positive history of other disease and taking medication. Fever as one of presenting symptom were noticed in 10 of 16 STAA patients. The laboratory results were similar with SAA or vSAA, had more frequent decreased serum albumin level and total iron binding capacity and higher CFU-GM. Patients with AAH often had similar clinical symptoms with SAA or vSAA. Although they were diagnosed retrospectively, identification of the pathogenesis and laboratory examination may help for the early diagnosis.


Chlamyweb Study I: rationale, design and acceptability of an internet-based chlamydia testing intervention.
In recent years, the internet has widely facilitated Chlamydia trachomatis home-sampling. In France (2012), the Chlamyweb Study evaluated an intervention (Chlamyweb) involving home-based self-sampling via the internet. One element of the study consisted of a randomised controlled trial (RCT), which is reported in detail elsewhere. The focus of this paper, however, is on describing the Chlamyweb Intervention and reporting on the non-RCT element of the evaluation of that intervention by the Chlamyweb Study. This involves (1) describing the design and roll-out of the Chlamyweb Intervention, (2) comparing the socio-behavioural profiles of the participants in the intervention with a nationally representative general population sample and (3) examining the factors that influence the acceptance and return of a self-sampling kit supplied to participants in the course of the intervention. Self-sampling kits were offered to sexually active people aged 18-24 years living on the mainland French. Participants' characteristics were compared with the general population to describe recruited and participant populations. Multivariate analyses by conditional logistic regression were performed to determine factors that were predictors of kit acceptation and use. 7215 people aged 18-24 years were included. Compared with the general population, Chlamyweb reached larger proportions of women, younger people and people with several partners in the previous year. 3372 (46.7%) agreed to receive a self-sampling kit and 2084 (61.8%) returned it, with more women doing so than men. The participation rate was associated with age, place of birth, occupational status, number of partners and condom use, differently for men and women. The offer of easy-to-use, self-sampling kits free of charge appeared to be a logistically feasible strategy for testing in France and reached a large and diverse population including individuals who have limited access to the traditional healthcare system. AFFSAPS n° IDRCB 0211-A01000-41; pre-results.


Rotational stability of a spinal pedicle screw/rod system.
Although the geometry of spinal instrumentation constructs may significantly affect efficacy, the variation in biomechanical data may not assist the clinician in an appropriate selection. The purpose of the present study was to quantify the effects of transverse fixators on rotational strength of a common pedicle-screw-with-rods system. Pedicle screws were mounted in blocks of polymethyl-methacrylate at angles to reproduce the configuration of placement in the human lumbar spine. Twenty cycles of +/- 12 N-m axial rotation moment was applied, and the steady-state response was used in the analysis. Configurations tested included both medial and lateral placement of longitudinal rods as well as the addition of one or two transverse rods. Up to a 20% difference in stiffness was noted between medial and lateral placement of longitudinal rods when no transverse rods were mounted. A maximum difference in flexibility of 6% was noted between the use of one and two transverse rods. For medially placed rods, a single transverse connector will add significant rotational stiffness even for shorter rod lengths; for laterally placed longitudinal rods, only the longer rod lengths need a transverse connector.


Analysis of a meningococcal meningitis outbreak in Niger - potential effectiveness of reactive prophylaxis.
Seasonal epidemics of bacterial meningitis in the African Meningitis Belt carry a high burden of disease and mortality. Reactive mass vaccination is used as a control measure during epidemics, but the time taken to gain immunity from the vaccine reduces the flexibility and effectiveness of these campaigns. Targeted reactive antibiotic prophylaxis could be used to supplement reactive mass vaccination and further reduce the incidence of meningitis, and the potential effectiveness and efficiency of these strategies should be explored. Data from an outbreak of meningococcal meningitis in Niger, caused primarily by Neisseria meningitidis serogroup C, is used to estimate clustering of meningitis cases at the household and village level. In addition, reactive antibiotic prophylaxis and reactive vaccination strategies are simulated to estimate their potential effectiveness and efficiency, with a focus on the threshold and spatial unit used to declare an epidemic and initiate the intervention. There is village-level clustering of suspected meningitis cases after an epidemic has been declared in a health area. Risk of suspected meningitis among household contacts of a suspected meningitis case is no higher than among members of the same village. Village-wide antibiotic prophylaxis can target subsequent cases in villages: across of range of parameters pertaining to how the intervention is performed, up to 220/672 suspected cases during the season are potentially preventable. On the other hand, household prophylaxis targets very few cases. In general, the village-wide strategy is not very sensitive to the method used to declare an epidemic. Finally, village-wide antibiotic prophylaxis is potentially more efficient than mass vaccination of all individuals at the beginning of the season, and than the equivalent reactive vaccination strategy. Village-wide antibiotic prophylaxis should be considered and tested further as a response against outbreaks of meningococcal meningitis in the Meningitis Belt, as a supplement to reactive mass vaccination.


A comprehensive situation assessment of injection practices in primary health care hospitals in Bangladesh.
Understanding injection practices is crucial for evidence-based development of intervention initiatives. This study explored the extent of injection use and injection safety practices in primary care hospitals in Bangladesh. The study employed both quantitative and qualitative research methods. The methods used were--a retrospective audit of prescriptions (n = 4320), focus group discussions (six with 43 participants), in-depth interviews (n = 38) with a range service providers, and systematic observation of the activities of injection providers (n = 120), waste handlers (n = 48) and hospital facilities (n = 24). Quantitative and qualitative data were assessed with statistical and thematic analysis, respectively, and then combined. As many as 78% of our study sample (n = 4230) received an injection. The most commonly prescribed injections (n = 3354) including antibiotics (78.3%), IV fluids (38.6%), analgesics/pain killers (29.4%), vitamins (26.7%), and anti-histamines (18.5%). Further, 43.7% (n = 1145) of the prescribed antibiotics (n = 2626) were given to treat diarrhea and 42.3% (n = 600) of IV fluids (n = 1295) were used to manage general weakness conditions. Nearly one-third (29.8%; n = 36/120) of injection providers reported needle-stick injuries in the last 6 months with highest incidences in Rajshahi division followed by Dhaka division. Disposal of injection needles, syringes and other materials was not done properly in 83.5% (n = 20/24) of the facilities. Health providers' safety concerns were not addressed properly; only 23% (n = 28/120) of the health providers and 4.2% (n = 2/48) of the waste handlers were fully immunized against Hepatitis B virus. Moreover, 73% (n = 87/120) of the injection providers and 90% (n = 43/48) of the waste handlers were not trained in injection safety practices and infection prevention. Qualitative data further confirmed that both providers and patients preferred injections, believing that they provide quick relief. The doctors' perceived injection use as their prescribing norm that enabled them to prove their professional credibility and to remain popular in a competitive health care market. Additionally, persistent pressure from hospital administration to use up injections before their expiry dates also influenced doctors to prescribe injections regardless of actual indications. As far as the patients and providers' safety is concerned, this study demonstrated a need for further research exploring the dynamics of injection use and safety in Bangladesh. In a context where a high level of injection use and unsafe practices were reported, immediate prevention initiatives need to be operated through continued intervention efforts and health providers' training in primary care hospitals in Bangladesh.


Physiotherapy students' attitudes towards and knowledge of older people.
The purpose of this study was to determine whether students' attitudes towards and knowledge of older people changed throughout the physiotherapy undergraduate program. Students' demographic information and attitudes towards and knowledge of older people were gathered via repeated question-responses over three points of time during the 4-year program. Validated instruments--the Geriatric Attitudinal Scale (GAS) and the Facts on Ageing Quiz 1 (FAQ1)--were used to measure participants' attitudes and knowledge of older people. The FAQ1 yielded two variables: knowledge as percentage of FAQ1 correct responses, and ignorance as percentage of FAQ1 Don't Know responses. The instruments were administered in Year 2 prior to the students' first clinical (Time 1), immediately after their first clinical (Time 2), and Year 4 just prior to completion of the program (Time 3). Changes over time were analysed using paired t-tests with significance set at p < 0.05. Participants initially demonstrated positive attitudes towards older people with a mean of 73.8% GAS positive responses with no significant change over time (p = 0.56). Initial knowledge about older people was poor with a mean of 43.6% FAQ1 correct responses which increased significantly over time to 51.7% (p = 0.0001). This improvement in knowledge was accompanied by a decrease in ignorance over the study period (p = 0.0001). While attitudes toward older people were positive and knowledge improved over time, the level of knowledge attained was below expectation for beginning practitioners. This finding has implications for the education and training of physiotherapy students.


Antihyperglycaemic activity of Asparagus racemosus roots is partly mediated by inhibition of carbohydrate digestion and absorption, and enhancement of cellular insulin action.
Asparagus racemosus roots have been shown to enhance insulin secretion in perfused pancreas and isolated islets. The present study investigated the effects of ethanol extracts of A. racemosus roots on glucose homeostasis in diabetic rats, together with the effects on insulin action in 3T3 adipocytes. When administered orally together with glucose, A. racemosus extract improved glucose tolerance in normal as well as in two types of diabetic rats. To investigate the possible effects on carbohydrate absorption, the sucrose content of the gastrointestinal tract was examined in 12 h fasted rats after an oral sucrose load (2.5 g/kg body weight). The extract significantly suppressed postprandial hyperglycaemia after sucrose ingestion and reversibly increased unabsorbed sucrose content throughout the gut. The extract also significantly inhibited the absorption of glucose during in situ gut perfusion with glucose. Furthermore, the extract enhanced glucose transport and insulin action in 3T3-L1 adipocytes. Daily administration of A. racemosus to type 2 diabetic rats for 28 d decreased serum glucose, increased pancreatic insulin, plasma insulin, liver glycogen and total oxidant status. These findings indicate that antihyperglycaemic activity of A. racemosus is partly mediated by inhibition of carbohydrate digestion and absorption, together with enhancement of insulin secretion and action in the peripheral tissue. Asparagus racemosus may be useful as a source of novel antidiabetic compounds or a dietary adjunct for the management of diabetes.


Health Care Utilization and Direct Medical Costs of Tennis Elbow: A Population-Based Study.
Tennis elbow is commonly encountered by physicians, yet little is known about the cost of treating this condition. The largest cost associated with treating tennis elbow is procedural intervention. Descriptive epidemiology study. Level 4. This retrospective population-based study reviewed patients who were treated for new-onset tennis elbow between January 1, 2003 and December 31, 2012. All patients were followed up through their medical and administrative records to identify health care encounters and interventions for tennis elbow. Unit costs for each health service/procedure were adjusted to nationally representative unit costs in 2013 inflation-adjusted dollars. In a cohort of 931 patients who had 2 or more clinical encounters for new-onset lateral epicondylosis during a 12-month period after initial diagnosis, 62% received a median of 3 physical therapy sessions (cost, $100/session) and 40% received a median of 1 steroid injection (cost, $82/injection). Only 4% of patients received surgical intervention with mean costs of $4000. The mean (median) total direct medical cost of services related to lateral epicondylosis for the entire cohort was $660 ($402) per patient over the 1-year period after diagnosis. Patients who continued to be treated conservatively between 6 and 12 months after diagnosis incurred relatively low median costs of $168 per patient. In this cohort, a second encounter with a physician for tennis elbow was a strong predictor of increased treatment cost due to a higher likelihood of specialist referral, use of physical therapy, or treatment with steroid injection. The majority of direct medical spending on tennis elbow occurs within the first 6 months of treatment, and relatively little expense occurs between 6 and 12 months after diagnosis unless a patient undergoes surgical intervention.


Evaluating simulation education via electronic surveys immediately following live critical events: a pilot study.
Simulation-based medical education has become popular in postgraduate training for medical emergencies; however, the direct impact on learners' clinical performances during live critical events is unknown. Our goal was to evaluate the perceived impact of simulation-based education on pediatric emergencies by auditing pediatric residents immediately after involvement in actual emergency clinical events. Weekly team-based pediatric simulation training for inpatient emergencies was implemented in an academic tertiary care hospital. Immediately after actual pediatric emergency events, each resident involved was audited regarding roles, performed tasks, and perceived effectiveness of earlier simulation-based education. The audit was performed by using a Likert scale. From September 2010 through August 2011, a total of 49 simulation sessions were held. During the same period, 27 pediatric emergency events occurred: 3 code events, 14 rapid response team activations, and 10 emergency transfers to the PICU. Forty-seven survey responses from 20 pediatric residents were obtained after the emergency clinical events. Fifty-three percent of residents felt well prepared, and 45% reported having experienced a similar simulation before the clinical event. A preceding similar simulation experience was perceived as helpful in improving clinical performance. Residents' confidence levels, however, did not differ significantly between those who reported having had a preceding similar simulation and those who had not (median of 4 vs median of 3; P=.16, Wilcoxon rank-sum test). A novel electronic survey was successfully piloted to measure residents' perceptions of simulation education compared with live critical events. Residents perceived that their experiences in earlier similar simulations positively affected their performances during emergencies.


Tolerance to high-intensity intermittent running exercise: do oxygen uptake kinetics really matter?
We examined the respective associations between aerobic fitness ([Formula: see text]max), metabolic control ([Formula: see text] kinetics) and locomotor function, and various physiological responses to high-intensity intermittent (HIT) running exercise in team sport players. Eleven players (30.5 ± 3.6 year) performed a series of tests to determine their [Formula: see text]max and the associated velocity (v[Formula: see text]max), maximal sprinting speed (MSS) and [Formula: see text] kinetics at exercise onset in the moderate and severe intensity domains, and during recovery ([Formula: see text] SEV). Cardiorespiratory variables, oxygenation and electromyography of lower limbs muscles and blood lactate ([La]) concentration were collected during a standardized HIT protocol consisting in 8 sets of 10, 4-s runs. During HIT, four players could not complete more than two sets; the others finished at least five sets. Metabolic responses to the two first sets of HIT were negatively correlated with [Formula: see text]max, v[Formula: see text]max, and [Formula: see text] SEV (r = -0.6 to -0.8), while there was no clear relationship with the other variables. [Formula: see text], oxygenation and [La] responses to the first two sets of HIT were the only variables that differed between the players which could complete at least five sets or those who could not complete more than two sets. Players that managed to run at least five sets presented, in comparison with the others, greater v[Formula: see text]max [ES = +1.5(0.4; 2.7), MSS(ES = +1.0(0.1; 1.9)] and training load [ES = +3.8 (2.8; 4.9)]. There was no clear between-group difference in any of the [Formula: see text] kinetics measures [e.g., ES = -0.1(-1.4; 1.2) for [Formula: see text] SEV]. While [Formula: see text]max and v[Formula: see text]max are likely determinant for HIT tolerance, the importance of [Formula: see text] kinetics as assessed in this study appears limited in the present population. Knowing the main factors influencing tolerance to HIT running exercise may assist practitioners in personalizing training interventions.


Differential expression of Ixodes ricinus salivary gland proteins in the presence of the Borrelia burgdorferi sensu lato complex.
In Europe, Ixodes ricinus is the main vector of Lyme borreliosis. Their salivary glands play a critical role in the biological success of ticks. To better understand the cross-talk between Borrelia burgdorferi and tick salivary glands, we analyzed protein expression in the salivary glands of I. ricinus adult ticks that were infected by various strains of the B. burgdorferi sl complex. iTRAQ allowed the identification of more than 120 proteins, providing the first proteomic data pertaining to I. ricinus salivary glands. Among these proteins, only 12 were modulated in the presence of various Borrelia strains. Most of them are up-regulated and are involved in cell defense and protein synthesis and processing. Down-regulated proteins are mostly implicated in the cytoskeleton. The DIGE analysis allowed us to identify 35 proteins and showed the down-regulation of 4 proteins. All 15 proteins were not modulated by all strains. Overall, these observations showed that the presence of Borrelia in tick salivary glands is a factor of stress for the protein machinery, and also that some Borrelia strains produce a dysregulation of cytoskeletal proteins. Interestingly, a protein from Borrelia, OspA, was found in infected salivary glands. The consequence of its presence in salivary glands is discussed. Lyme borreliosis is still the most prevalent arthropod-borne disease in the temperate regions of the northern hemisphere. The geographical distribution of Lyme borreliosis is expanding, especially towards higher altitudes and latitudes. Human pathogenic spirochetes causing Lyme borreliosis belong to the B. burgdorferi sensu lato complex. They are extracellular pathogens transmitted to humans through the bite of Ixodes spp. ticks. The bioactive molecules present in tick saliva not only promote tick feeding, but also create an advantageous microenvironment at the tick bite site for survival and replication of Borrelia bacteria. Investigation of the tick-host-pathogen interface would provide new strategies to control tick-borne infections. We chose to analyze the interaction of several strains of the B. burgdorferi sensu lato complex with I. ricinus salivary glands. We also investigated the presence of bacterial proteins in salivary glands. For these purposes, we undertook a proteomic study implying the complementary approaches of iTRAQ and DIGE. Our study allowed identifying several salivary markers of infection that were shown to vary according to the strain. Moreover, OspA, a bacterial protein was shown to be expressed in salivary glands and may be implied in the pathogenicity of some Borrelia strains.


Quantifying Ocular Surface Inflammation and Correlating It With Inflammatory Cell Infiltration In Vivo: A Novel Method.
The purpose of this study was to develop a novel, objective, and semiautomated method to quantify conjunctival redness by correlating measured redness with standard clinical redness and symptom scales and inflammatory cell infiltration. Eleven outpatients presenting with mild to severe conjunctival hyperemia were included in the study. Clinical examination included patient history; visual analogue score (VAS) for ocular symptoms; 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) for quality of life/vision; photographs of the anterior segment graded for conjunctival hyperemia, using Efron, relative redness of image (RRI), and edge feature (EF) scales; and conjunctival impression cytology analyzed by flow cytometry. Differences between affected and unaffected eyes were evaluated, and correlations among questionnaire scores, ocular hyperemia grading scores, and assessment of biological markers were performed. Visual analogue score (P < 0.0001), Efron scale (P = 0.0003), RRI scores (P = 0.0004), and EF scores (P < 0.0001) and the percentage of granulocytes (defined as cluster of differentiation [CD] 45dim; P = 0.0080) were significantly higher in affected eyes. Conversely, the percentage of CD45bright leukocytes was reduced in affected eyes (P = 0.0054). Both the RRIs and EFs were positively correlated with VAS, Efron scale, percentages of conjunctival granulocytes, and CD45brightCD3neg cells, whereas they were negatively correlated with the percentage of CD45brightCD3pos cells. Edge feature and RRI were correlated (Spearman r = 0.78, P < 0.0001). Ocular redness is a cardinal sign driving clinical judgment in highly prevalent ocular disorders; hence, we suggest that our semiautomated and reproducible method may represent a helpful tool in the follow-up of these patients. Italian Abstract.


Patterns of healthy lifestyle and positive health attitudes in older Europeans.
To determine (i) the extent to which recommended lifestyle healthy behaviors are adopted and the existence of positive attitudes to health; (ii) the relative influence of socio-demographic variables on multiple healthy lifestyle behaviors and positive attitudes to health; (iii) the association between healthy lifestyle behaviors and positive attitudes to health. Two distinct healthy behavioral measures were developed: (i) healthy lifestyles based on physical activity, no cigarette smoking, no/moderate alcohol drinking, maintaining a "healthy" weight and having no sleeping problems and (ii) positive health attitudes based on having positive emotional attitudes, such as: self-perceived good health status, being calm, peaceful and happy for most of the time, not expecting health to get worse and regular health check-ups. A composite healthy lifestyle index, ranging from 0 (none of behaviors met) to 5 (all behaviors met) was calculated by summing up the individual's scores for the five healthy lifestyle items. Afterwards, each individual's index was collapsed into three levels: 0-2 equivalent to 'level 1' (subjectively regarded as 'too low'), a score of 3 equivalent to 'level 2' ('fair') and 4-5 as 'level 3' satisfactory 'healthy lifestyle' practices. The same procedure was applied to the positive health attitudes index. Multinomial logistic regression analyses by a forward selection procedure were used to calculate the adjusted odds ratio (OR) with 95% confidence interval (95% CI). A multi-national sample consisting of 638 older Europeans from 8 countries, aged 65-74 and 75+, living alone or with others. Maintaining a "healthy" weight was the most frequently cited factor in the healthy lifestyles index and therefore assumed to be the most important to the older Europeans in the study; positive attitudes to health were relatively low; participants achieved a 'satisfactory' level for healthy lifestyles index (level 3) more frequently than a satisfactory level for positive attitudes to health; having a satisfactory 'healthy lifestyle' was directly related to having a satisfactory level of positive attitudes to health based on the positive health attitudes index; income and geographical location in Europe appeared to be key predictors for meeting both the recommended healthy lifestyle factors in the index and having positive health attitudes however, the composition and nature of the study sample should be taken into consideration when considering the impact of the location on healthy lifestyles and attitudes to health across Europe.


Potent In Vivo NK Cell-Mediated Elimination of HIV-1-Infected Cells Mobilized by a gp120-Bispecific and Hexavalent Broadly Neutralizing Fusion Protein.
Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir.IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir.


Sucking, not milk, is important for the rapid learning of nipple-search odors in newborn rabbits.
Newborn rabbits are only nursed once a day for 3 to 4 min and are completely dependent on a pheromone on the mother's ventrum for the release of nipple-search behavior and sucking. However, if the mother's ventrum is perfumed, pups can be conditioned in just one 3-min nursing session to respond with nipple searching to the novel odorant. To define more precisely the reinforcing properties of the nursing situation supporting such rapid learning, odor conditioning was conducted in independent groups of 2-day-old pups after successively eliminating potential reinforcing stimuli such as the doe's behavior, milk ingestion, nipple-search behavior, or sucking nipples. All experimental groups showed significant conditioning compared to control groups subjected to similar treatments on unscented does, with the strength of conditioning indicating that behavior of the doe, milk consumption, or arousal during performance of the search behavior were not major reinforcers, but rather the opportunity to suck nipples. Thus, this study suggests intraoral stimulation associated with sucking to be an important reinforcer in this paradigm, as for early olfactory learning in other young mammals.


The epidemiology of schistosomiasis in Egypt: Menofia Governorate.
Health questionnaires and parasitologic examinations of urine and stool were performed upon a stratified random sample of 10,899 individuals from 1,537 households in 27 rural communities in Menofia Governorate in Egypt in 1992 to investigate the prevalence of, risk factors for, and changing pattern of infection with Schistosoma sp. in the governorate. A subset, every fifth household, or 1,480 subjects, had physical and ultrasound examinations to investigate prevalence of and risk factors for morbidity. The prevalence of S. mansoni ranged from 0.3% to 72.9% and averaged 28.5%. The geometric mean egg count was 81.3 eggs/gram of stool. Age-stratified prevalence and intensity of infection was 30-40% and 60-80 eggs/gram of stool from the age of 10 onward; males had higher infection rates and ova counts than females in all age groups > 10 years old. Schistosoma haematobium was rare, being consequential in only 1 community. Risk factors for S. mansoni infection were male gender; age > 10 years; living in smaller communities; exposures to canal water; history of or treatment for schistosomiasis or blood in the stool; detection of splenomegaly by either physical or ultrasound; and ultrasound-detected periportal fibrosis (PPF). The more severe grades of PPF were rarely (21 of 1,450 examinations) detected. Risk factors for morbidity, i.e., ultrasound-detected PPF, were similar to those for infection. Schistosoma mansoni has almost totally replaced S. haematobium in Menofia. The prevalence of S. mansoni in rural communities remains high and average intensities of infection are moderate. The association of morbidity with schistosomal infection was variable and is obviously markedly influenced by both the frequent use of antischistosomal chemotherapy in communities in Menofia and by the prevalence of complications from chronic viral hepatitis in the population: hepatomegaly did not correlate with infection; PPF and splenomegaly, however, were related to S. mansoni infection in both individuals and communities.


Gait variability is altered in older adults when listening to auditory stimuli with differing temporal structures.
Gait variability in the context of a deterministic dynamical system may be quantified using nonlinear time series analyses that characterize the complexity of the system. Pathological gait exhibits altered gait variability. It can be either too periodic and predictable, or too random and disordered, as is the case with aging. While gait therapies often focus on restoration of linear measures such as gait speed or stride length, we propose that the goal of gait therapy should be to restore optimal gait variability, which exhibits chaotic fluctuations and is the balance between predictability and complexity. In this context, our purpose was to investigate how listening to different auditory stimuli affects gait variability. Twenty-seven young and 27 elderly subjects walked on a treadmill for 5 min while listening to white noise, a chaotic rhythm, a metronome, and with no auditory stimulus. Stride length, step width, and stride intervals were calculated for all conditions. Detrended Fluctuation Analysis was then performed on these time series. A quadratic trend analysis determined that an idealized inverted-U shape described the relationship between gait variability and the structure of the auditory stimuli for the elderly group, but not for the young group. This proof-of-concept study shows that the gait of older adults may be manipulated using auditory stimuli. Future work will investigate which structures of auditory stimuli lead to improvements in functional status in older adults.


Promoting pepper (Capsicum annuum) photosynthesis via chloroplast ultrastructure and enzyme activities by optimising the ammonium to nitrate ratio.
Optimal plant growth in many species is achieved when the two major forms of N are supplied at a particular ratio. In this pot experiment, the effects of five different ammonium:nitrate ratios (ANRs) (0:100, 12.5:87.5, 25:75, 37.5:62.5, and 50:50) on photosynthesis efficiency in chilli pepper (Capsicum annuum L.) plants were evaluated. The results showed that an ANR of 25:75 increased the contents of chl a, leaf area and dry matter, whereas chl b content was not affected by the ANRs. Regarding chlorophyll fluorescence, an ANR of 25:75 also enhanced the actual photochemical efficiency, photochemical quenching and maximum photosynthetic rate. However, the 0:100 and 50:50 ANRs resulted in higher values for nonphotochemical quenching. An inhibition of maximal photochemical efficiency was found when 50% NH4+ was supplied at the later stage of plant growth. The addition of 25% or 37.5% NH4+ was beneficial for gas exchange parameters and the 25% NH4+ optimised the thylakoid of chloroplasts. Compared with nitrate alone, 12.5–50% NH4+ upregulated glutamate dehydrogenase (GDH), the large subunit and the small subunit of Rubisco. It can be concluded that the 25:75 ANR accelerated N assimilation through active GDH, which provides a material basis for chloroplast and Rubisco formation, resulting in the increased photosynthetic rate and enhanced growth in chilli pepper.