A multi-proxy Late-glacial palaeoenvironmental record from Lake Bled, Slovenia

This study investigates the palaeoecological record (δ¹⁸O, δ¹³C, pollen, plant macrofossils, chironomids and cladocera) at Lake Bled (Slovenia) sedimentary core to better understand the response of terrestrial and aquatic ecosystems to Late-glacial climatic fluctuations. The multi-proxy record suggests that in the Oldest Dryas, the landscape around Lake Bled was rather open, presumably because of the cold and dry climate, with a trend towards wetter conditions, as suggested by an increase in tree pollen as well as chironomid and cladocera faunas typical for well-oxygenated water. Climatic warming at the beginning of the Late-glacial Interstadial at ca. 14,800 cal yr BP is suggested by an increase in the δ¹⁸O value, the appearance of Betula and Larix pollen and macrofossils, and a warmth-adapted chironomid fauna. With further warming at ca. 13,800 cal yr BP, broad-leaved tree taxa (Quercus, Tilia, Ulmus), Artemisia, and Picea increase, whereas chironomid data (Cricotopus B) suggest lowering of lake levels. After 12,800 cal yr BP (and throughout the Younger Dryas), the climate was colder and drier, as indicated by lower δ¹⁸O values, decline of trees, increase of microscopic charcoal, xerophytes and littoral chironomids. A warmer climate, together with the spread of broad-leaved tree taxa and a deeper, more productive lake, mark the onset of the Late-glacial/Holocene transition. These results suggest that terrestrial and aquatic ecosystems at Lake Bled were very dynamic and sensitive to Late-glacial climatic fluctuations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Guest editors: K. Buczkó, J. Korponai, J. Padisák & S. W. Starratt Palaeolimnological Proxies as Tools of Environmental Reconstruction in Fresh Water     

ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression

Introduction

Autoantibodies against citrullinated peptides/proteins (ACPA) are found in approximately 75% of the sera of patients with rheumatoid arthritis (RA). The RA-specific ACPA are frequently present prior to disease onset and their presence associates with a more erosive disease course. ACPA can therefore be used to aid the diagnosis and prognosis of RA. Recently, it became clear that ACPA are very heterogeneous, both in an individual patient and among different patients. The aim of this study was to investigate whether clinically meaningful ACPA profiles exist in early RA patients.

Methods

Twenty citrullinated peptides and the corresponding non-citrullinated control peptides were immobilized on microarray sensor chips. Sera from 374 early arthritis patients were analyzed by surface plasmon resonance imaging (iSPR) of biomolecular interactions on the sensor chip.

Results

Cluster analysis of the reactivities with the citrullinated peptides, after subtraction of the reactivities with the corresponding control peptides confirmed the heterogeneity of the ACPA response in RA and revealed 12 distinct ACPA profiles. The association of the 5 most frequent profiles with clinical features at diagnosis and during the disease course was examined, showing no statistically significant associations.

Conclusions

Compared to the detection of ACPA in RA sera by CCP-based assays, ACPA profiling in early arthritis patients did not reveal associations with disease activity and progression scores.     

Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study

Background

Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not.

Methods

We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls.

Results

The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR.

Conclusions

Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined.

Trial Registration

The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB12610000830099     

Evaluation of stability and size distribution of sunflower oil-coated micro bubbles for localized drug delivery

Background

In recent years magnesium alloys have been intensively investigated as potential resorbable materials with appropriate mechanical and corrosion properties. Particularly in orthopedic research magnesium is interesting because of its mechanical properties close to those of natural bone, the prevention of both stress shielding and removal of the implant after surgery.

Methods

ZEK100 plates were examined in this in vitro study with Hank's Balanced Salt Solution under physiological conditions with a constant laminar flow rate. After 14, 28 and 42 days of immersion the ZEK100 plates were mechanically tested via four point bending test. The surfaces of the immersed specimens were characterized by SEM, EDX and XRD.

Results

The four point bending test displayed an increased bending strength after 6 weeks immersion compared to the 2 week group and 4 week group. The characterization of the surface revealed the presence of high amounts of O, P and Ca on the surface and small Mg content. This indicates the precipitation of calcium phosphates with low solubility on the surface of the ZEK100 plates.

Conclusions

The results of the present in vitro study indicate that ZEK100 is a potential candidate for degradable orthopedic implants. Further investigations are needed to examine the degradation behavior.     

Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity

Introduction

B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.

Methods

In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.

Results

Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.

Conclusion

By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.     

Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway

Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XY(B6) mice impaired testis differentiation, but no ovarian tissue developed. If, however, a Y(AKR) chromosome replaced the Y(B6) chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/- B6 XY(AKR), Wt1+/- B6 XY(AKR), B6 XY(POS), and B6 XY(AKR) fetuses. We propose that Wt1(B6) and Sf1(B6) are hypomorphic alleles of testis-determining pathway genes and that Wnt4(B6) is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1(B6) and/or Sf1(B6) alleles that compromise testis differentiation and a Wnt4(B6) allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a "weak" Sry allele, such as the one on the Y(POS) chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal.     

Intestinal calcium and phosphate transport in genetic hypophosphatemic mice

Serum phosphate, serum calcium, intestinal phosphate and intestinal calcium transport were measured in normal ($\text{C57BL}\text{6J}$ +/Y) and genetic (X-linked) hypophosphatemic mice ($\text{C57BL}\text{6J}\text{Hyp}\text{Y}$). The hypophosphatemic mice had low serum phosphorus levels and dramatically decreased intestinal phosphate transport compared with normal controls. On the other hand, normal and hypophosphatemic mice had equivalent levels of intestinal calcium transport. The hypophosphatemic mice did illustrate a slightly decreased serum calcium concentration, however. Administration of 1,25-dihydroxy-vitamin D₃, the principal active metabolite of vitamin D, stimulated intestinal calcium transport but not intestinal phosphate transport in the genetic hypophosphatemic mice. The results obtained are consistent with the hypothesis that the primary metabolic disturbance in familial hypophosphatemia involves a defect in phosphate transport mechanisms.     

The mouse mutation claw paw: forelimb deformity and delayed myelination throughout the peripheral nervous system.

We describe a murine autosomal recessive mutation claw paw (gene symbol clp), which in homozygous clp/clp mice produces striking abnormalities of limb posture within the first one or two postnatal days. Affected animals have delayed and abnormal myelination in the peripheral nervous system but not in the central nervous system, and also have persistently blocked myelination of small caliber axons that are myelinated in normal mice. Both abnormalities suggest that an important effect of the clp mutation is to impair the putative signaling mechanism by which an axon instructs a Schwann cell whether or not to myelinate it. The early onset of behavioral abnormalities in clp/clp mutant mice, as well as certain other features of the disorder, suggest that some effects of the clp gene are not accounted for by the pathological findings. The clp gene has been mapped to chromosome 7 near the Gpi-1 locus.