The V-region disease hypothesis: evidence from autoimmune encephalomyelitis.

Experimental allergic encephalomyelitis has been shown to have an immunological basis. In fact, the disease can be induced by T cells specific for myelin basic protein, a molecule found in abundance in the central nervous system. In this article, Ellen Heber-Katz and Hans Acha-Orbea discuss the T-cell receptor (TCR) repertoire of the encephalitogenic T-cell response, and show that a limited V gene pool, in fact a single V beta and two V alpha families, are being used by the PL/J and B10.PL mice and by every rat strain examined, even though the antigenic determinants and the major histocompatibility complex (MHC) molecules are different in all cases. This extraordinary finding suggests that the TCR is involved in encephalitogenicity in a way that not only involves the recognition of antigen in association with MHC, but also as an effector molecule that results in encephalitis. If this is true, it implies that TCRs, in general, play more than one role in mammalian physiology.

Infestation and natural parasitism of aphids in single and mixed pastures of black oats and ryegrass

Some species of aphids are major pests on cereal crops and grass pastures. Usually these pests are not adequately controlled in pasture lands that become sources of aphid infestations to cereal crops. The dynamics of aphids and the incidence of natural enemies are less known in pasture systems than in cereal fields. The objective of this work was to assess the aphid infestation and natural aphid parasitism in different pasture composition. Three hypotheses were tested: 1- the aphid species composition in pastures may vary according to the cereal species in the field; 2- the mixture of two plant species can modify the amount and diversity of aphids; 3- the plant species composition of pasture fields influences the parasitism of aphids. Empirical data were obtained from three Poaceae fields: black oats (Avena strigosa L.), ryegrass (Lolium multiflorum L.), and a mixed field of black oats and ryegrass. The most abundant aphid species was Rhopalosiphum padi followed by Sitobion avenae. Plant species composition increases the amount and the parasitism rates of aphids. The mixture of heavily infested black oats with a poorly infested ryegrass resulted in reduction of aphid infestation in comparison with heavily-infested single plant species field. This is possible because the conditions are favorable for the development of parasitoid populations. Aphidius colemani was the main parasitoid found in these areas.

Single mothers and incentives to work: The French experience

This paper analyzes the effect of the 1998 reform of the French single parents allowanceon the labor supply of single mothers with very young children. The reform aimed atencouraging participation by allowing eligible single parents to accumulate benefits andlabor earnings for a limited period of time. Using data from the French EmploymentSurvey, the analysis shows that single mothers affected by the reform had experienced asignificant increase in their employment rate four years after the reform wasimplemented. During the same period, the employment rate of married mothers withyoung children did not experience a significant change, suggesting that at least part ofthe increase was a consequence of the reform. These results provide some evidence thatbenefit schedules that provide financial incentives to work can have significant effectsin getting single moms back to work, even in the presence of very young children.

State of Iowa’s Single Audit Report for the year ended June 30, 2008

State of Iowa’s Single Audit Report for the year ended June 30, 2008

The alternatively spliced domain TnFnIII A1A2 of the extracellular matrix protein tenascin-C suppresses activation-induced T lymphocyte proliferation and cytokine production.

Several lines of evidences have suggested that T cell activation could be impaired in the tumor environment, a condition referred to as tumor-induced immunosuppression. We have previously shown that tenascin-C, an extracellular matrix protein highly expressed in the tumor stroma, inhibits T lymphocyte activation in vitro, raising the possibility that this molecule might contribute to tumor-induced immunosuppression in vivo. However, the region of the protein mediating this effect has remained elusive. Here we report the identification of the minimal region of tenascin-C that can inhibit T cell activation. Recombinant fragments corresponding to defined regions of the molecule were tested for their ability to inhibit in vitro activation of human peripheral blood T cells induced by anti-CD3 mAbs in combination with fibronectin or IL-2. A recombinant protein encompassing the alternatively spliced fibronectin type III domains of tenascin-C (TnFnIII A-D) vigorously inhibited both early and late lymphocyte activation events including activation-induced TCR/CD8 down-modulation, cytokine production, and DNA synthesis. In agreement with this, full length recombinant tenascin-C containing the alternatively spliced region suppressed T cell activation, whereas tenascin-C lacking this region did not. Using a series of smaller fragments and deletion mutants issued from this region, we have identified the TnFnIII A1A2 domain as the minimal region suppressing T cell activation. Single TnFnIII A1 or A2 domains were no longer inhibitory, while maximal inhibition required the presence of the TnFnIII A3 domain. Altogether, these data demonstrate that the TnFnIII A1A2 domain mediate the ability of tenascin-C to inhibit in vitro T cell activation and provide insights into the immunosuppressive activity of tenascin-C in vivo.

Systematic study of the static electrical properties of the CO molecule: influence of the basis set size and correlation energy

The influence of the basis set size and the correlation energy in the static electrical properties of the CO molecule is assessed. In particular, we have studied both the nuclear relaxation and the vibrational contributions to the static molecular electrical properties, the vibrational Stark effect (VSE) and the vibrational intensity effect (VIE). From a mathematical point of view, when a static and uniform electric field is applied to a molecule, the energy of this system can be expressed in terms of a double power series with respect to the bond length and to the field strength. From the power series expansion of the potential energy, field-dependent expressions for the equilibrium geometry, for the potential energy and for the force constant are obtained. The nuclear relaxation and vibrational contributions to the molecular electrical properties are analyzed in terms of the derivatives of the electronic molecular properties. In general, the results presented show that accurate inclusion of the correlation energy and large basis sets are needed to calculate the molecular electrical properties and their derivatives with respect to either nuclear displacements or/and field strength. With respect to experimental data, the calculated power series coefficients are overestimated by the SCF, CISD, and QCISD methods. On the contrary, perturbation methods (MP2 and MP4) tend to underestimate them. In average and using the 6-311 + G(3df) basis set and for the CO molecule, the nuclear relaxation and the vibrational contributions to the molecular electrical properties amount to 11.7%, 3.3%, and 69.7% of the purely electronic μ, α, and β values, respectively

How T cell receptors interact with peptide-MHCs: A multiple steered molecular dynamics study.

The T-cell receptor (TCR) interaction with antigenic peptides (p) presented by the major histocompatibility complex (MHC) molecule is a key determinant of immune response. In addition, TCR-pMHC interactions offer examples of features more generally pertaining to protein-protein recognition: subtle specificity and cross-reactivity. Despite their importance, molecular details determining the TCR-pMHC binding remain unsolved. However, molecular simulation provides the opportunity to investigate some of these aspects. In this study, we perform extensive equilibrium and steered molecular dynamics simulations to study the unbinding of three TCR-pMHC complexes. As a function of the dissociation reaction coordinate, we are able to obtain converged H-bond counts and energy decompositions at different levels of detail, ranging from the full proteins, to separate residues and water molecules, down to single atoms at the interface. Many observed features do not support a previously proposed two-step model for TCR recognition. Our results also provide keys to interpret experimental point-mutation results. We highlight the role of water both in terms of interface resolvation and of water molecules trapped in the bound complex. Importantly, we illustrate how two TCRs with similar reactivity and structures can have essentially different binding strategies. Proteins 2011; © 2011 Wiley-Liss, Inc.

Oral Antibiotics for Fever in Low-Risk Neutropenic Patients With Cancer: A Double-Blind, Randomized, Multicenter Trial Comparing Single Daily Moxifloxacin With Twice Daily Ciprofloxacin Plus Amoxicillin/Clavulanic Acid Combination Therapy--EORTC Infectious Diseases Group Trial XV.

PURPOSE This double-blind, multicenter trial compared the efficacy and safety of a single daily oral dose of moxifloxacin with oral combination therapy in low-risk febrile neutropenic patients with cancer. PATIENTS AND METHODS Inclusion criteria were cancer, febrile neutropenia, low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score > 20, ability to swallow, and ≤ one single intravenous dose of empiric antibiotic therapy before study drug treatment initiation. Early discharge was encouraged when a set of predefined criteria was met. Patients received either moxifloxacin (400 mg once daily) monotherapy or oral ciprofloxacin (750 mg twice daily) plus amoxicillin/clavulanic acid (1,000 mg twice daily). The trial was designed to show equivalence of the two drug regimens in terms of therapy success, defined as defervescence and improvement in clinical status during study drug treatment (< 10% difference). Results Among the 333 patients evaluated in an intention-to-treat analysis, therapy success was observed in 80% of the patients administered moxifloxacin and in 82% of the patients administered combination therapy (95% CI for the difference, -10% to 8%, consistent with equivalence). Minor differences in tolerability, safety, and reasons for failure were observed. More than 50% of the patients in the two arms were discharged on protocol therapy, with 5% readmissions among those in either arm. Survival was similar (99%) in both arms. CONCLUSION Monotherapy with once daily oral moxifloxacin is efficacious and safe in low-risk febrile neutropenic patients identified with the help of the MASCC scoring system, discharged early, and observed as outpatients.

A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance.

We report the study of a large American family displaying autosomal dominant retinitis pigmentosa with reduced penetrance, a form of hereditary retinal degeneration. Although the inheritance pattern and previous linkage mapping pointed to the involvement of the PRPF31 gene, extensive screening of all its exons and their boundaries failed in the past to reveal any mutation. In this work, we sequenced the entire PRPF31 genomic region by both the classical Sanger method and ultrahigh throughput (UHT) sequencing. Among the many variants identified, a single-base substitution (c.1374+654C>G) located deep within intron 13 and inside a repetitive DNA element was common to all patients and obligate asymptomatic carriers. This change created a new splice donor site leading to the synthesis of two mutant PRPF31 isoforms, degraded by nonsense-mediated mRNA decay. As a consequence, amounts of PRPF31 mRNA derived from the mutant allele were very reduced, with no evidence of mutant proteins being synthesized. Our results indicate that c.1374+654C>G causes retinitis pigmentosa via haploinsufficiency, similar to the vast majority of PRPF31 mutations described so far. We discuss the potential of UHT sequencing technologies in mutation screening and the continued identification of pathogenic splicing mutations buried deep within intronic regions.

Waveform inversion of crosshole georadar data: influence of source wavelet variability and the suitability of a single wavelet assumption

Waveform-based tomographic imaging of crosshole georadar data is a powerful method to investigate the shallow subsurface because of its ability to provide images of electrical properties in near-surface environments with unprecedented spatial resolution. A critical issue with waveform inversion is the a priori unknown source signal. Indeed, the estimation of the source pulse is notoriously difficult but essential for the effective application of this method. Here, we explore the viability and robustness of a recently proposed deconvolution-based procedure to estimate the source pulse during waveform inversion of crosshole georadar data, where changes in wavelet shape with location as a result of varying near-field conditions and differences in antenna coupling may be significant. Specifically, we examine whether a single, average estimated source current function can adequately represent the pulses radiated at all transmitter locations during a crosshole georadar survey, or whether a separate source wavelet estimation should be performed for each transmitter gather. Tests with synthetic and field data indicate that remarkably good tomographic reconstructions can be obtained using a single estimated source pulse when moderate to strong variability exists in the true source signal with antenna location. Only in the case of very strong variability in the true source pulse are tomographic reconstructions clearly improved by estimating a different source wavelet for each transmitter location.

Fuel metabolism during exercise in euglycaemia and hyperglycaemia in patients with type 1 diabetes mellitus--a prospective single-blinded randomised crossover trial.

Aims/hypothesis We assessed systemic and local muscle fuel metabolism during aerobic exercise in patients with type I diabetes at euglycaemia and hyperglycaemia with identical insulin levels.Methods This was a single-blinded randomised crossover study at a university diabetes unit in Switzerland. We studied seven physically active men with type I diabetes (mean +/- SEM age 33.5 +/- 2.4 years, diabetes duration 20.1 +/- 3.6 years, HbA(1c) 6.7 +/- 0.2% and peak oxygen uptake [VO2peak] 50.3 +/- 4.5 ml min(-1) kg(-1)). Men were studied twice while cycling for 120 min at 55 to 60% of VO2peak, with a blood glucose level randomly set either at 5 or 11 mmol/l and identical insulinaemia. The participants were blinded to the glycaemic level; allocation concealment was by opaque, sealed envelopes. Magnetic resonance spectroscopy was used to quantify intramyocellular glycogen and lipids before and after exercise. Indirect calorimetry and measurement of stable isotopes and counter-regulatory hormones complemented the assessment of local and systemic fuel metabolism.Results The contribution of lipid oxidation to overall energy metabolism was higher in euglycaemia than in hyperglycaemia (49.4 +/- 4.8 vs 30.6 +/- 4.2%; p<0.05). Carbohydrate oxidation accounted for 48.2 +/- 4.7 and 66.6 +/- 4.2% of total energy expenditure in euglycaemia and hyperglycaemia, respectively (p<0.05). The level of intramyocellular glycogen before exercise was higher in hyperglycaemia than in euglycaemia (3.4 +/- 0.3 vs 2.7 +/- 0.2 arbitrary units [AU]; p<0.05). Absolute glycogen consumption tended to be higher in hyperglycaemia than in euglycaemia (1.3 +/- 0.3 vs 0.9 +/- 0.1 AU). Cortisol and growth hormone increased more strongly in euglycaemia than in hyperglycaemia (levels at the end of exercise 634 52 vs 501 +/- 32 nmol/l and 15.5 +/- 4.5 vs 7.4 +/- 2.0 ng/ml, respectively; p<0.05).Conclusions/interpretation Substrate oxidation in type I diabetic patients performing aerobic exercise in euglycaemia is similar to that in healthy individuals revealing a shift towards lipid oxidation during exercise. In hyperglycaemia fuel metabolism in these patients is dominated by carbohydrate oxidation. Intramyocellular glycogen was not spared in hyperglycaemia.

Adenocarcinoma of the pancreas: Comparative single centre analysis between ductal and mucinous type.

1. Background¦Adenocarcinomas of the pancreas are exocrine tumors, originate from ductal system, including two morphologically distinct entities: the ductal adenocarcinoma and mucinous adenocarcinoma. Ductal adenocarcinoma is by far the most frequent malignant tumor in the pancreas, representing at least about 90% of all pancreas cancers. It is associated with very poor prognosis, due to the fact that actually there are no any biological markers or diagnostic tools for identification of the disease at an early stage. Most of the time the disease is extensive with vascular and nerves involvement or with metastatic spread at the time of diagnosis (1). The median survival is less than 5% at 5 years, placing it, at the fifth leading cause of death by cancer in the world (2). The mucinous form of pancreatic adenocarcinoma is less frequent, and seems to have a better prognosis with about 57% survival at 5 years (1)(3)(4).¦Each morphologic type of pancreatic adenocarcinoma is associated with particular preneoplastic lesions. Two types of preneoplastic lesions are described: firstly, pancreatic intra-epithelial neoplasia (PanIN) which affects the small and peripheral pancreatic ducts, and the intraductal papillary-mucinous neoplasm (IPMN) interested the main pancreatic ducts and its principal branches. Both of preneoplastic lesions lead by different mechanisms to the pancreatic adenocarcinoma (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).¦The purpose of our study consists in a retrospective analysis of various clinical and histo-morphological parameters in order to assess a difference in survival between these two morphological types of pancreatic adenocarcinomas.¦1.2 Material and methods¦We conducted a retrospective analysis including 35 patients, (20 men and 15 women), beneficed the surgical treatment for pancreas adenocarcinoma at the Surgical Department of University Hospital in Lausanne. The patients involved in our study have been treated between 2003 and 2008, permitting at least 5-years mean follow up. For each patient the following parameters were analysed: age, gender, type of operation, type of preneoplastic lesions, TNM stage, histological grade of the tumor, vascular invasion, lymphatic and perineural invasion, resection margins, and adjuvant treatment.¦The results from these observations were included in a univariate and multivariate statistical analysis and compared with overall survival, as well as specific survival for each morphologic subtype of adenocarcinoma.¦As a low number of mucinous adenocarcinomas (n=5) was insufficient to conduct a pertinent statistical analysis, we compared the data obtained from adenocarcinomas developed on PanIN with adenocarcinomas developed on IPMN including both, ductal or mucinous types.¦1.3 Result¦Our results show that adenocarcinomas developed on pre-existing IPMN including both morphologic types (ductal and mucinous form) are associated with a better survival and prognosis than adenocarciomas developed on PanIN.¦1.4 Conclusion¦This study reflects that the most relevant parameter in survival in pancreatic adenocarcinoma seems to be the type of preneoplastic lesion. The significant difference in survival was noted between adenocarcinomas developing on PanIN as compared to adenocarcinomas developed on IPMN precursor lesions. Ductal adenocarcinomas developped on IPMN present significantly longer survival than those developed on PanIN lesions (P value= 0,01). Therefore we can suggest that the histological type of preneoplastic lesion rather than the histological type of adenocarcinoma should be the determinant prognosis factor in survival of pancreatic adenocarcinoma.

The meiosis-specific recombinase hDmc1 forms ring structures and interacts with hRad51.

Eukaryotic cells encode two homologs of Escherichia coli RecA protein, Rad51 and Dmc1, which are required for meiotic recombination. Rad51, like E.coli RecA, forms helical nucleoprotein filaments that promote joint molecule and heteroduplex DNA formation. Electron microscopy reveals that the human meiosis-specific recombinase Dmc1 forms ring structures that bind single-stranded (ss) and double-stranded (ds) DNA. The protein binds preferentially to ssDNA tails and gaps in duplex DNA. hDmc1-ssDNA complexes exhibit an irregular, often compacted structure, and promote strand-transfer reactions with homologous duplex DNA. hDmc1 binds duplex DNA with reduced affinity to form nucleoprotein complexes. In contrast to helical RecA/Rad51 filaments, however, Dmc1 filaments are composed of a linear array of stacked protein rings. Consistent with the requirement for two recombinases in meiotic recombination, hDmc1 interacts directly with hRad51.

Critical appraisal of single port access cholecystectomy.

BACKGROUND: Single port access (SPA) cholecystectomy is a new concept in laparoscopic surgery. A review of existing results was performed to evaluate critically the current state of SPA with specific reference to feasibility, safety, learning curve, indications and cost-effectiveness. METHODS: All papers identified in MEDLINE until 15 February 2010 and all other relevant papers obtained from cited references were reviewed, without any language restriction. Case reports and series of fewer than three patients were excluded. RESULTS: After selection, 24 studies including 895 patients were analysed. None was randomized. Feasibility seems to be established, with a conversion rate of 2 per cent. SPA was not standardized and there was much technical variation. The learning curve could not be determined. Median follow-up time was 3 (range 0.25-12) months. The overall published complication rate was 5.4 per cent and the biliary complication rate 0.7 per cent. The rate of umbilical complications ranged from 2 to 10 per cent. CONCLUSION: SPA cholecystectomy seems feasible, but standardization, safety and the real benefits for patients need further assessment. Uncontrolled wide adoption of this approach may be responsible for a rise in biliary complications.