Molecular fingerprints resolve affinities of Rhynie chert organic fossils.

The affinities of extinct organisms are often difficult to resolve using morphological data alone. Chemical analysis of carbonaceous specimens can complement traditional approaches, but the search for taxon-specific signals in ancient, thermally altered organic matter is challenging and controversial, partly because suitable positive controls are lacking. Here, we show that non-destructive Fourier Transform Infrared Spectroscopy (FTIR) resolves in-situ molecular fingerprints in the famous 407 Ma Rhynie chert fossil assemblage of Aberdeenshire, Scotland, an important early terrestrial Lagerstätte. Remarkably, unsupervised clustering methods (principal components analysis and K-mean) separate the fossil spectra naturally into eukaryotes and prokaryotes (cyanobacteria). Additional multivariate statistics and machine-learning approaches also differentiate prokaryotes from eukaryotes, and discriminate eukaryotic tissue types, despite the overwhelming influence of silica. We find that these methods can clarify the affinities of morphologically ambiguous taxa; in the Rhynie chert for example, we show that the problematic "nematophytes" have a plant-like composition. Overall, we demonstrate that the famously exquisite preservation of cells, tissues and organisms in the Rhynie chert accompanies similarly impressive preservation of molecular information. These results provide a compelling positive control that validates the use of infrared spectroscopy to investigate the affinity of organic fossils in chert.

[Lipids and their correlation with vitamin D in the indigenous populations of Russia European North].

The aim of our research was to investigate the level of 25-OH vitamin D in blood plasma of indigenous inhabitants of Russia European North. The study showed that there was wide spreading of vitamin D deficiency among northerners especially in teenager. The significant reduction of 25-OH vitamin D3 was revealed in the inhabitants of Far North in March. It is shown that there is correlation of the vitamin D with total cholesterol, apolipoprotein A, high and low density lipoproteins and vitamin A and E.

Presentation of a self-peptide for in vivo tolerance induction of CD4+ T cells is governed by a processing factor that maps to the class II region of the major histocompatibility complex locus.

Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 61-80 peptide failed to induce elimination of autoreactive CD4+ T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of Ld 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4+ T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.

[Vitamin D level in the indigenous populations of Russia European North].

The aim of our research was to investigate the level of 25-OH vitamin D3 in blood plasma of indigenous inhabitants of Russia European North. The study showed that there was wide spreading of vitamin D deficiency among northerners especially in teenager. The significant reduction of level of 25-OH vitamin D3 was revealed in the inhabitants of Far North in March.

Sex differences in contextual fear conditioning are associated with differential ventral hippocampal extracellular signal-regulated kinase activation.

Although sex differences have been reported in hippocampal-dependent learning and memory, including contextual fear memories, the underlying molecular mechanisms contributing to such differences are not well understood. The present study examined the extent to which sex differences in contextual fear conditioning are related to differential activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), a protein kinase critically involved in memory formation. We first show that male rats exhibit more long-term retention of contextual fear conditioning than female rats. During a tone test, females spent more time freezing than males, although both sexes exhibited robust retention of auditory fear learning. Using Western blot analysis, we then show that phosphorylated ERK levels in ventral, but not dorsal, hippocampus are higher in males than females, relative to same-sex controls, 60 minutes after fear conditioning. Post-conditioning increases in ERK activation were observed in the amygdala in both males and females, suggesting a selective effect of sex on hippocampal ERK activation. Together, these findings suggest that differential activation of the ERK signal transduction pathway in male and female rats, particularly in the ventral hippocampus, is associated with sex differences in contextual fear.

Strategic considerations for the sustainable remediation of nuclear installations.

Nuclear sites around the world are being decommissioned and remedial actions are being undertaken to enable the sites or parts of the sites to be reused. Although this is relatively straightforward for most sites, experience has suggested that preventative action is needed to minimise the impact of remediation activities on the environment and the potential burden to future generations. Removing all contamination in order to make a site suitable for any use generates waste and has associated environmental, social and economic detriments and benefits that should be taken into account. Recent experience of OECD Nuclear Energy Agency (NEA) member countries in the remediation of contaminated land, predominantly contaminated soil and groundwater, on nuclear sites during decommissioning has been assessed by an NEA task group. The experience was used to identify strategic considerations for nuclear site remediation, to consider the application of sustainability principles to nuclear site remediation, to describe good practice, and to make recommendations for further research and development. The key aspects that were identified were that 1) site remediation should be sustainable by resulting in an overall net benefit; and 2) an adaptive approach is essential in order to take into account the inherent uncertainty associated with the decommissioning and site remediation timescales. A report describing the findings was published by OECD/NEA in 2016. The conclusions provide insights to decision makers, regulators, implementers and stakeholders involved in nuclear site decommissioning so that they can achieve sustainable remediation of nuclear sites, now and in the future.

Performance measurement of a Canadian provincial tuberculosis programme: Manitoba, 2008-2012.

BACKGROUND: Performance measurement assists tuberculosis (TB) programmes in understanding areas of strength and weakness, and planning for improvements. Canada currently does not have a national comprehensive system for the measurement and analysis of TB programme performance. OBJECTIVE: To analyse the performance of a Canadian provincial TB programme using measures and targets based on those published by the US Centers for Disease Prevention and Control for 2015. DESIGN: Using provincial surveillance data from the Canadian province of Manitoba, we analysed key programme performance outcome measures (treatment completion, early detection, human immunodeficiency virus [HIV] testing, paediatric TB, retreatment, and contact elicitation and assessment) for people diagnosed with TB between 2008 and 2010. RESULTS: Significant outcome variation was found between Indigenous and non-Indigenous populations as well as within populations. The reporting rate of HIV testing was low. High rates of paediatric TB among Indigenous populations, particularly in rural areas, were found. Significantly better performance in HIV testing and reporting as well as in contact investigation was found for rural compared with urban Indigenous populations. Foreign-born persons had the lowest contact assessment rate. CONCLUSION: This study of TB programme performance in Manitoba demonstrates the viability of the approach in the Canadian context, and could help to identify key areas for TB programme improvement.

IFN-γ promoter polymorphisms do not affect QuantiFERON® TB Gold In-Tube test results in a Canadian population.

BACKGROUND: Several studies have shown polymorphisms within the interferon-gamma (IFN-γ) promoter influence cytokine expression. The interferon-gamma release assay (IGRA) relies on the ability to produce IFN-γ in response to tuberculosis (TB) specific antigens. This study determined the relationship between the IFN-γ +874 A/T promoter polymorphism and the performance of the QuantiFERON®-TB Gold In-Tube (QFT-GIT) test in an ethnically diverse Canadian population. METHODS: A total of 190 participants were categorised into three groups based on history of and exposure to TB: active TB (n = 55), TB exposed (n = 55) and presumably TB unexposed controls (n = 80). All participants underwent QFT-GIT testing, and DNA was extracted from whole blood and probed for polymorphism at position +874 (T/A) of intron 1 of IFN-γ. Statistical relationships between the QFT-GIT results, polymorphisms and demographic data were evaluated. RESULTS: IFN-γ +874 genotype frequencies among the entire study population (n = 190) were A/A (45.8%), T/A (39.5%), and T/T (14.7%). Among the three study groups, there was no correlation between QFT-GIT results and the IFN-γ +874 A/T genotype, and no correlation of genotype with IFN-γ production in response to either Mycobacterium tuberculosis antigens or mitogenic stimulation. CONCLUSION: Our results indicate that the IFN-γ +874 promoter polymorphism does not influence QFT-GIT performance in this study population.

Urticaria and large cell undifferentiated carcinoma of lung.

The association of urticaria with internal cancer is known mostly with lymphoreticular system malignancies. Rarely, it occurs with cancer of lung, mostly with adenocarcinoma or small cell carcinoma. We report a unique occurrence of urticaria on a patient who suffered from large cell undifferentiated carcinoma of lung. Only the treatment for malignancy relieved the patient from his long standing cutaneous manifestation.

Self determinant selection and acquisition of the autoimmune T cell repertoire.

Autologous proteins are continuously processed and presented in the form of peptides associated with self major histocompatibility (MHC) molecules at the surface of antigen-presenting cells for interaction with autoreactive T cells. During thymic selection, the presentation of self peptides is an essential element in the establishment of the T cell repertoire. Developing T cells which recognize self peptide/self MHC complexes with sufficient affinity are clonally deleted. However, we and others have recently demonstrated that a variety of self peptides, despite their high binding affinity to MHC molecules, never reach the threshold of presentation to ensure negative selection (cryptic self peptides). This mechanism may have been selected to avoid excessive purging of T cell repertoire during ontogeny. However, T cells directed to cryptic self determinants represent a continuous threat for the initiation of autoimmunity in adults. Supporting this view, recent studies have documented the involvement of cryptic self peptide presentation in different autoimmune diseases. In this article, we examine the factors that govern the selection of self peptides for presentation to autoreactive T cells in vivo and discuss their contribution to both the induction and the maintenance of self tolerance. In addition, we analyze the mechanisms by which the hierarchy of determinants on a self protein can be disrupted, thereby leading to the presentation of previously cryptic self peptides and the induction of an autoimmune T-cell-mediated process.

Aboriginals with multiple sclerosis: HLA types and predominance of neuromyelitis optica.

BACKGROUND: MS is common in people of northern European ethnicity who live in northern geographic areas; however, MS is rarely identified among aboriginal peoples living in the same areas. OBJECTIVES: To determine the prevalence, clinical features, HLA type, and viral infections associated with MS among aboriginals in Manitoba, Canada. METHODS: A retrospective study was performed in which the clinical features of all aboriginal patients with MS together with HLA type and human herpesvirus-6, HIV-1, human T-cell lymphotropic virus-1, and endogenous retrovirus associated with MS (MSRV) infections were analyzed and compared with results from nonaboriginal patients with MS. RESULTS: Seven aboriginals with MS were identified with a period prevalence among aboriginals of 40:100,000. Clinical features included relapsing-remitting (n = 6) or primary progressive (n = 1) phenotypes with aggressive disease courses and frequent involvement of optic nerves and spinal cord (n = 5) compared with nonaboriginal patients. Autopsy of one patient showed necrosis and eosinophil infiltrates in a cervical spinal cord lesion and a demyelinated optic nerve. Analysis of HLA alleles at the DRB1 and DQB1 loci indicated that the HLA types detected were common in aboriginals, but there were no HLA alleles previously associated with the development of MS. Analysis of the copy number of MSRV did not show differences among aboriginals and nonaboriginals with or without MS. CONCLUSIONS: Aboriginals of Algonkian background are at increased risk for an aggressive type of MS, resembling neuromyelitis optica, which is resistant to conventional MS treatments and occurs independently of HLA alleles previously associated with MS.

Gross hematuria in residents of long-term-care facilities.

PURPOSE: To describe the epidemiology and characteristics of gross hematuria in elderly residents of nursing homes and to identify the associations of gross hematuria with urinary infection and the potential contribution of urinary infection to morbidity. PATIENTS AND METHODS: This was a prospective, descriptive study of episodes of gross hematuria identified by the nursing staffs at two long-term-care facilities over 2 years. Episodes were characterized with respect to patient variables, presence of bacteriuria, duration of hematuria, therapeutic interventions, and genitourinary investigations. Clinical and serologic criteria were used to identify invasive infection. RESULTS: The incidence of gross hematuria was 31/100,000 resident days. Bacteriuria was present in 58 (74%) of 78 episodes with evaluable cultures. Fifty-two (61%) episodes lasted more than 24 hours, 25 (29%) were temporally associated with fever, and antimicrobials were given for 53 (61%) episodes. Gross hematuria occurred more frequently in men than in women and was more frequently associated with fever in men. Twenty-four (28%) episodes occurred in subjects with indwelling catheters, 30 (34%) in subjects with known genitourinary abnormalities, 26 (30%) in subjects with no genitourinary investigations, and 4 (4.6%) in subjects with genitourinary investigations but no abnormalities identified. No adverse clinical outcomes were identified in patients in whom antimicrobial therapy was not initiated. The maximal estimated incidence of invasive urinary infection associated with hematuria was 5.8/100,000 resident days, and of bacterial hemorrhagic cystitis, 6.3/100,000 resident days. CONCLUSIONS: These data suggest that underlying genitourinary abnormalities are present in most elderly institutionalized subjects with gross hematuria when genitourinary investigations are performed. Although bacteriuria is usually present, urinary infection, by itself, is an infrequent cause of gross hematuria. Afebrile hematuria without irritative symptoms probably does not require antimicrobial therapy. A standard approach to this clinical problem in the institutionalized elderly should be developed to optimize patient management and appropriate use of antimicrobial therapy.

Febrile urinary infection in the institutionalized elderly.

PURPOSE: Bacteriuria is common among institutionalized elderly populations, but the contribution of urinary infection to febrile morbidity is unknown because of difficulties in clinical ascertainment. This study was undertaken to febrile morbidity using both clinical and serologic criteria. METHODS: Episodes of fever in residents of two long-term care institutions were identified prospectively for 2 years. Serum and urine specimens were obtained initially and at 4 weeks. The proportion of episodes attributable to urinary infection was determined by both standard clinical criteria proposed for use in these populations and serum antibody response to uropathogens. RESULTS: For 372 fewer episodes, 211 met clinical criteria for infection: 147 (40%) of the respiratory tract; 26 (7%) of the genitourinary tract; 25 (6%) of the gastrointestinal tract; and 13 (3%) of skin and soft tissue. Of the remaining 161 fever episodes, 2 (1%) were noninfectious and 159 (43%) were of unknown origin. The prevalence of bacteriuria for residents with nongenitourinary sources of fever varied from 32% to 75%. An antibody response meeting serologic criteria for urinary infection occurred in 26 (8.3%) of 314 episodes with paired sera obtained; 10 (43%) of 23 identified clinically as genitourinary infection, 14 (11%) of 132 unknown, 1 (4%) of 25 gastrointestinal, and 1 (0.8%) of 122 respiratory. The positive predictive value of bacteriuria for febrile urinary infection identified by clinical criteria was was 11% (95% confidence interval [CI] 4%, 18%) and identified by serologic criteria was 12% (95% CI 7%, 17%). CONCLUSIONS: Urinary infection contributes to less than 10% of episodes of clinically significant fever in this high-prevalence bacteriuric population. A restrictive clinical definition for genitourinary infection has poor sensitivity and specificity compared with serologic criteria for identification of fever of urinary source, and bacteriuria has a low predictive value for identifying febrile urinary infection.

Direct evidence for in vivo induction of CD8+ cytotoxic T cells directed to donor MHC class I peptides following mouse allotransplantation.

There is accumulating evidence indicating that the T cell response to donor major histocompatibility complex (MHC) peptides plays a crucial role in graft rejection. We and others previously demonstrated the involvement of MHC class-II-restricted recognition of donor MHC class I and II peptides by alloreactive CD4+ T helper cells in graft rejection. Here we studied the in vivo induction of CD8+ cytotoxic T lymphocytes (CTL) directed to donor MHC class I peptides following allotransplantation in the mouse. To address this question, BALB/c irradiated splenocytes (H-2d) (Kd, A(d), E(d), Ld, Dd) were injected into Ld-deficient BALB/c-dm2 (dm2) mutant mice (Kd, A(d), E(d), -, Dd). Nine days after allogeneic cell transplant, recipient lymph node T cells were tested for cytolytic activity using peritoneal macrophages as targets. We observed that in addition to BALB/c targets, dm2 macrophages could also be lysed but only when incubated with a dominant peptide on donor Ld molecule, Ld 61-80. This response was abolished by anti-CD8 but not anti-CD4 monoclonal antibodies. In addition, after immunization of dm2 mice with the peptide Ld 61-80, alloreactive CTL were generated in vivo and shown to destroy allogeneic donor BALB/c target cells in the absence of exogenously added peptide. We conclude that after allotransplantation, concomitant in vivo priming of alloreactive CD8+ CTL by donor MHC class I peptides occurs through both direct and indirect pathways of allorecognition.

Induction of T cell responses to a self-antigen following allotransplantation.

T cell tolerance to self-antigens is established through the recognition by immature T cells of dominant self-peptides presented in association with self-MHC molecules in the developing thymus (negative selection). The self-peptide Dd 61-80 is dominant in syngeneic BALB/c mice (H2d). T cell tolerance to Dd 61-80 in this mouse strain resulted in the absence of T cell proliferation following in vivo priming with Dd 61-80 peptide. Here, we show that transplantation of BALB/c mice with allogeneic B10.A (H2a) splenocytes led to an autoimmune T cell response toward the dominant self-peptide Dd 61-80. No T cell responses to Dd 61-80 peptide were observed after transplantation of C57BL/6 (H2b) splenocytes into BALB/c recipients. In addition, we provide evidence indicating that the breakdown of tolerance to Dd 61-80 self-peptide resulted from the presentation of the donor crossreactive peptide Kk 61-80 at the surface of recipient antigen-presenting cells. Taken together, our results suggest that following allotransplantation, T cell responses to donor antigens could spread to crossreactive determinants on self-proteins, thus perpetuating and amplifying the rejection process and presumably initiating tissue-specific autoimmune disorders.

Manifest refraction versus autorefraction for patients with subfoveal choroidal neovascularization.

PURPOSE: To compare the results from manifest refraction using trial lenses and a standard visual acuity protocol to results from autorefraction for obtaining refractive error and best corrected visual acuity in patients enrolled in a randomized clinical trial. METHODS: During a 4-month period, 29 patients with subfoveal choroidal neovascularization (CNV), who were enrolled in the Submacular Surgery Trials (SSTs) Pilot Study at the Wilmer Ophthalmological Institute, gave verbal consent to participate in this study. Best corrected visual acuity was obtained using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts and standardized room lighting after performance of manifest refraction, according to the SST protocol, and autorefraction. Refractive error (spherical equivalent) and visual acuity scores were obtained in both eyes of all patients. RESULTS: On average, manifest refraction gave a spherical equivalent that was 1.04 D more plus than autorefraction (95% limits of agreement = 0.74, 1.34). On average, the visual acuity score was 1.5 letters better after manifest refraction than after autorefraction (95% limits of agreement = 0, 3.0). The comparison of the two methods of refraction was subdivided according to visual acuity level and eye disease (age-related macular degeneration or ocular histoplasmosis syndrome). CONCLUSIONS: Despite large differences in spherical equivalent between manifest refraction and autorefraction, the visual acuity scores were close (mean difference, 1.5 letters). Other studies comparing subjective refraction and autorefraction have shown similar results. Autorefraction in patients with subfoveal CNV may be a satisfactory alternative to manifest refraction in clinical trials and field studies in which best corrected visual acuity is of interest.

A new arthropod from the Silurian Konservat-Lagerstätte of Herefordshire, UK.

A small, non-biomineralized, macrophagous arthropod with chelicerate affinities, Offacolus kingi gen. et sp. nov., from the Silurian (Wenlock Series) of Herefordshire, UK, is described. The dorsal exoskeleton comprises an arch-like cephalic shield, a thorax of three free tergites and a triangular posterior tagma of five fused tergites, the last with a stout postero-dorsally directed medial spine. Seven pairs of appendages beneath the cephalic shield surround a postero-medially sited oral cavity on the ventral surface of the head. Appendages I and, probably II are uniramous and project antero-ventrally; I was sensory and II sensory and/or ambulatory. Appendages III-VI are biramous, each with an antero-ventrally projecting ramus and a robust, highly geniculate, horizontally oriented ramus that projects through an anterior gape. The former rami were ambulatory and the latter have spinose terminal podomeres and functioned as a unit for trapping food and transferring it towards the oral cavity. Appendage VII, which is probably uniramous, is posteroventrally directed and flap like. Each tergite of the thorax and posterior tagma covers at least a pair (probably two pairs) of probably biramous appendages with each ramus flap like and setose.