Torolf Moen

A Y chromosome census of the British Isles

The degree of population replacement in the British Isles associated with cultural changes has been extensively debated. Recent work has demonstrated that comparisons of genetic variation in the British Isles and on the European Continent can illuminate specific demographic processes in the history of the British Isles. For example, Wilson et al. used the similarity of Basque and Celtic Y chromosomes to argue for genetic continuity from the Upper Palaeolithic to the present in the paternal history of these populations (see also ). Differences in the Y chromosome composition of these groups also suggested genetic signatures of Norwegian influence in the Orkney Islands north of the Scottish mainland, an important center of Viking activities between 800 and 1300 A.D. More recently, Weale et al. argued for substantial Anglo-Saxon male migration into central England based on the analysis of eight British sample sets collected on an east-west transect across England and Wales. To provide a more complete assessment of the paternal genetic history of the British Isles, we have compared the Y chromosome composition of multiple geographically distant British sample sets with collections from Norway (two sites), Denmark, and Germany and with collections from central Ireland, representing, respectively, the putative invading and the indigenous populations. By analyzing 1772 Y chromosomes from 25 predominantly small urban locations, we found that different parts of the British Isles have sharply different paternal histories; the degree of population replacement and genetic continuity shows systematic variation across the sampled areas.

The peopling of Europe and the cautionary tale of Y chromosome lineage R-M269

Recently, the debate on the origins of the major European Y chromosome haplogroup R1b1b2-M269 has reignited, and opinion has moved away from Palaeolithic origins to the notion of a younger Neolithic spread of these chromosomes from the Near East. Here, we address this debate by investigating frequency patterns and diversity in the largest collection of R1b1b2-M269 chromosomes yet assembled. Our analysis reveals no geographical trends in diversity, in contradiction to expectation under the Neolithic hypothesis, and suggests an alternative explanation for the apparent cline in diversity recently described. We further investigate the young, STR-based time to the most recent common ancestor estimates proposed so far for R-M269-related lineages and find evidence for an appreciable effect of microsatellite choice on age estimates. As a consequence, the existing data and tools are insufficient to make credible estimates for the age of this haplogroup, and conclusions about the timing of its origin and dispersal should be viewed with a large degree of caution.

Cutaneous T cell lymphoma and graft-versus-host disease : a comparison of in vivo effects of extracorporeal photochemotherapy on Foxp3+ regulatory T cells.

Extracorporeal photochemotherapy (ECP) is a well established treatment for both cutaneous T cell lymphoma (CTCL) and graft-versus-host disease (GVHD). However, the general effector mechanism is not fully settled. Twenty-four patients with CTCL and 14 patients with GVHD were included to assess the relative numbers of regulatory T cells (Treg) and any change in the serum cytokine profile during 6 months of ECP therapy. The relative amount of Treg cells was twice as high in CTCL compared to GVHD and healthy controls. TGF-beta was on average three times higher in GVHD than in CTCL. Both patient groups had a small but significant increase in TGF-beta after treatment. Our results indicate a strengthened Treg function as a result of ECP. Elevated TGF-beta may indicate high Treg activation in GVHD, whereas an increased number of Treg cells in CTCL could be interpreted as a response that is involved in down-regulating the lymphoma cells.

The Role of Recent Admixture in Forming the Contemporary West Eurasian Genomic Landscape

Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups [1-7]. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook [8-11]. Here, using recently described haplotype-based techniques [11], we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200 CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1,500 years are likely to have maintained differentiation among groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia.Summary Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups [1, 2, 3, 4, 5, 6, 7]. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook [8, 9, 10, 11]. Here, using recently described haplotype-based techniques [11], we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200 CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1,500 years are likely to have maintained differentiation among groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia.

Bronchoalveolar lavage fluid IFN- γ + Th17 cells and regulatory T cells in pulmonary sarcoidosis

In sarcoidosis, increased Th17 cell fractions have been reported in bronchoalveolar lavage fluid, and elevated numbers of Th17 cells producing IFN-γ have been observed in peripheral blood. The balance between Th1, Th17, and FoxP3+ CD4+ T cell subsets in sarcoidosis remains unclear. Bronchoalveolar lavage fluid cells, from 30 patients with sarcoidosis, 18 patients with other diffuse parenchymal lung diseases, and 15 healthy controls, were investigated with flow cytometry for intracellular expression of FoxP3. In a subset of the patients, expression of the cytokines IL17A and IFN-γ was investigated. The fractions of FoxP3+ CD4+ T cells and Th17 cells were both lower in sarcoidosis compared to controls (P = 0.017 and P = 0.011, resp.). The proportion of Th17 cells positive for IFN-γ was greater in sarcoidosis than controls (median 72.4% versus 31%, P = 0.0005) and increased with radiologic stage (N = 23, rho = 0.45, and P = 0.03). IFN-γ + Th17 cells were highly correlated with Th1 cells (N = 23, rho = 0.64, and P = 0.001), and the ratio of IFN-γ + Th17/FoxP3+ CD4+ T cells was prominently increased in sarcoidosis. IFN-γ + Th17 cells may represent a pathogenic subset of Th17 cells, yet their expression of IFN-γ could be a consequence of a Th1-polarized cytokine milieu. Our results indicate a possible immune cell imbalance in sarcoidosis.

In Vitro Experiments Demonstrate that Monocytes and Dendritic Cells are Rendered Apoptotic by Extracorporeal Photochemotherapy, but Exhibit Unaffected Surviving and Maturing Capacity after 30 Gy Gamma Irradiation

Extracorporeal photochemotherapy (ECP) has been shown to induce apoptosis in lymphocytes. Until recently the prevailing opinion has been that the monocytes were mainly not affected by this treatment. This study has investigated the effect of ECP and gamma irradiation on monocytes and immature dendritic cells (DC) in vitro and followed the ability of the cells to differentiate and survive post treatment. ECP induced apoptosis in lymphocytes, monocytes and immature DC within 72 h following treatment, in contrast to 30 Gy gamma irradiation, which seemed mainly to affect lymphocytes. The minority of the surviving ECP‐treated monocytes presented a reduced ability to differentiate into immature DC within this time frame. We also demonstrated that immature DC after ECP‐treatment lost their normal ability to mature on stimulation with lipopolysaccharide. As monocytes and immature DC seem to have a reduced ability to differentiate after ECP‐treatment, it is suggested that the therapeutic effect of ECP is caused by in vivo effects of reinfused apoptotic cells, rather than by infusion of monocytes induced to differentiate into immature DC.

An e-learning course in medical immunology: Does it improve learning outcome?

Background: E-learning is used by most medical students almost daily and several studies have shown e-learning to improve learning outcome in small-scale interventions. However, few studies have explored the effects of e-learning in immunology. Aim: To study the effect of an e-learning package in immunology on learning outcomes in a written integrated examination and to examine student satisfaction with the e-learning package. Methods: All second-year students at a Norwegian medical school were offered an animated e-learning package in basic immunology as a supplement to the regular teaching. Each students log-on-time was recorded and linked with the students score on multiple choice questions included in an integrated end-of-the-year written examination. Student satisfaction was assessed through a questionnaire. Results: The intermediate-range students (interquartile range) on average scored 3.6% better on the immunology part of the examination per hour they had used the e-learning package (p = 0.0046) and log-on-time explained 17% of the variance in immunology score. The best and the less skilled students’ examination outcomes were not affected by the e-learning. The e-learning was well appreciated among the students. Conclusion: Use of an e-learning package in immunology in addition to regular teaching improved learning outcomes for intermediate-range students.

Agreement of specific IgE and skin prick test in an unselected cohort of two-year-old children

The objective of this study was to evaluate the agreement between specific IgE (sIgE) and skin prick test (SPT), and the possible association between total IgE concentration and allergy-related disorders, when performed in an unselected cohort of 353 two-year olds. Median total IgE was within the reference value for two-year-old children regardless of the presence or absence of allergy-related disorders. 18.7% of the children had one or more positive reactions to SPT and/or sIgE in a panel of 12 allergens. Agreement between SPT and sIgE was variable, being best for peanut and poorest for milk. Conclusion: In young children total IgE is of limited value when evaluating allergy-related disorder. The lack of agreement among the positive tests of the sIgE and SPT for some allergens imply that these tests should not be used interchangeably, and both tests should probably be used complementarily when diagnosing atopic sensitization in small children.

Six months of diazoxide treatment at bedtime in newly diagnosed subjects with type 1 diabetes does not influence parameters of β-cell function and autoimmunity, but improves glycemic control.

OBJECTIVE Continuous β-cell rest with diazoxide preserves residual endogenous insulin production in type 1 diabetes. However, side effects have hampered therapeutic usefulness. In a double-blind study, we tested whether lower, intermittent dosing of diazoxide had beneficial effects on insulin production, metabolic control, and autoimmunity markers in the absence of side effects. RESEARCH DESIGN AND METHODS Forty-one newly diagnosed type 1 diabetic patients were randomized to 6 months of treatment with placebo or 100 mg diazoxide at bedtime. A1C, C-peptide (fasting and glucagon stimulated), and FoxP3+ regulatory T-cells (Tregs) were measured. Patients were followed for 6 months after intervention. RESULTS Of six dropouts, three were due to perceived side effects; one subject in the diazoxide group experienced rash, another dizziness, and one in the placebo group sleep disturbance. Adverse effects in others were absent. Diazoxide treatment reduced A1C from 8.6% at baseline to 6.0% at 6 months and 6.5% at 12 months. Corresponding A1C value in the placebo arm were 8.3, 7.3, and 7.5% (P < 0.05 for stronger reduction in the diazoxide group). Fasting and stimulated C-peptide decreased during 12 months similarly in both arms (mean −0.30 and −0.18 nmol/l in the diazoxide arm and −0.08 and −0.09 nmol/l in the placebo arm). The proportion of Tregs was similar in both arms and remained stable during intervention but was significantly lower compared with nondiabetic subjects. CONCLUSIONS Six months of low-dose diazoxide was without side effects and did not measurably affect insulin production but was associated with improved metabolic control.

Can maternal antiphospholipid antibodies predict the birth of a small-for-gestational age child?

Background. The aim of this study was to examine the relationship between the maternal level of antiphospholipid antibodies (aPA) measured by anticardiolipin antibodies (aCL) and fetal growth retardation (SGA).