Holocene environment of Central Kamchatka, Russia: Implications from a multi-proxy record of Two-Yurts Lake

© 2015 Elsevier B.V. Within the scope of Russian-German palaeoenvironmental research, Two-Yurts Lake (TYL, Dvuh-Yurtochnoe in Russian) was chosen as the main scientific target area to decipher Holocene climate variability on Kamchatka. The 5. ×. 2 km large and 26 m deep lake is of proglacial origin and situated on the eastern flank of Sredinny Ridge at the northwestern end of the Central Kamchatka Valley, outside the direct influence of active volcanism. Here, we present results of a multi-proxy study on sediment cores, spanning about the last 7000 years. The general tenor of the TYL record is an increase in continentality and winter snow cover in conjunction with a decrease in temperature, humidity, and biological productivity after 5000-4500. cal. yrs. BP, inferred from pollen and diatom data and the isotopic composition of organic carbon. The TYL proxy data also show that the late Holocene was punctuated by two colder spells, roughly between 4500 and 3500 cal. yrs. BP and between 1000 and 200 cal. yrs. BP, as local expressions of the Neoglacial and Little Ice Age, respectively. These environmental changes can be regarded as direct and indirect responses to climate change, as also demonstrated by other records in the regional terrestrial and marine realm. Long-term climate deterioration was driven by decreasing insolation, while the short-term climate excursions are best explained by local climatic processes. The latter affect the configuration of atmospheric pressure systems that control the sources as well as the temperature and moisture of air masses reaching Kamchatka

Changes in temperature and water depth of a small mountain lake during the past 3000 years in Central Kamchatka reflected by a chironomid record

© 2016 Elsevier Ltd and INQUA.We investigated chironomid assemblages of a well-dated sediment core from a small seepage lake situated at the eastern slope of the Central Kamchatka Mountain Chain, Far East Russia. The chironomid fauna of the investigated Sigrid Lake is dominated by littoral taxa that are sensitive to fluctuations of the water level. Two groups of taxa interchangeably dominate the record responding to the changes in the lake environment during the past 2800 years. The first group of littoral phytophilic taxa includes Psectrocladius sordidellus-type, Corynoneura arctica-type and Dicrotendipes nervosus-type. The abundances of the taxa from this group have the strongest influence on the variations of PCA 1, and these taxa mostly correspond to low water levels, moderate temperatures and slightly acidified conditions. The second group of taxa includes Microtendipes pedellus-type, Tanytarsus lugens-type, and Tanytarsus pallidicornis-type. The variations in the abundances of these taxa, and especially of M. pedellus-type, are in accordance with PCA 2 and correspond to the higher water level in the lake, more oligotrophic and neutral pH conditions. Water depths (WD) were reconstructed, using a modern chironomid-based temperature and water depth calibration data set (training set) and inference model from East Siberia (Nazarova et al., 2011). Mean July air temperatures (T July) were inferred using a chironomid-based temperature inference model based on a modern calibration data set for the Far East (Nazarova et al., 2015). The application of transfer functions resulted in reconstructed T July fluctuations of approximately 3 °C over the last 2800 years. Low temperatures (11.0-12.0 °C) were reconstructed for the periods between ca 1700 and 1500 cal yr BP (corresponding to the Kofun cold stage) and between ca 1200 and 150 cal yr BP (partly corresponding to the Little Ice Age [LIA]). Warm periods (modern T July or higher) were reconstructed for the periods between ca 2700 and 1800 cal yr BP, 1500 and 1300 cal yr BP and after 150 cal yr BP. WD reconstruction revealed that the lake level was lower than its present level at the beginning of the record between ca 2600 and 2300 cal yr BP and ca 550 cal yr BP. Between ca 2300 and 700 cal yr BP as well as between 450 and 150 cal yr BP, the lake level was higher than it is today, most probably reflecting more humid conditions

Changes in temperature and water depth of a small mountain lake during the past 3000 years in Central Kamchatka reflected by a chironomid record

© 2016 Elsevier Ltd and INQUA We investigated chironomid assemblages of a well-dated sediment core from a small seepage lake situated at the eastern slope of the Central Kamchatka Mountain Chain, Far East Russia. The chironomid fauna of the investigated Sigrid Lake is dominated by littoral taxa that are sensitive to fluctuations of the water level. Two groups of taxa interchangeably dominate the record responding to the changes in the lake environment during the past 2800 years. The first group of littoral phytophilic taxa includes Psectrocladius sordidellus-type, Corynoneura arctica-type and Dicrotendipes nervosus-type. The abundances of the taxa from this group have the strongest influence on the variations of PCA 1, and these taxa mostly correspond to low water levels, moderate temperatures and slightly acidified conditions. The second group of taxa includes Microtendipes pedellus-type, Tanytarsus lugens-type, and Tanytarsus pallidicornis-type. The variations in the abundances of these taxa, and especially of M. pedellu s-type, are in accordance with PCA 2 and correspond to the higher water level in the lake, more oligotrophic and neutral pH conditions. Water depths (WD) were reconstructed, using a modern chironomid-based temperature and water depth calibration data set (training set) and inference model from East Siberia (Nazarova et al., 2011). Mean July air temperatures (T July) were inferred using a chironomid-based temperature inference model based on a modern calibration data set for the Far East (Nazarova et al., 2015). The application of transfer functions resulted in reconstructed T July fluctuations of approximately 3 °C over the last 2800 years. Low temperatures (11.0–12.0 °C) were reconstructed for the periods between ca 1700 and 1500 cal yr BP (corresponding to the Kofun cold stage) and between ca 1200 and 150 cal yr BP (partly corresponding to the Little Ice Age [LIA]). Warm periods (modern T July or higher) were reconstructed for the periods between ca 2700 and 1800 cal yr BP, 1500 and 1300 cal yr BP and after 150 cal yr BP. WD reconstruction revealed that the lake level was lower than its present level at the beginning of the record between ca 2600 and 2300 cal yr BP and ca 550 cal yr BP. Between ca 2300 and 700 cal yr BP as well as between 450 and 150 cal yr BP, the lake level was higher than it is today, most probably reflecting more humid conditions

Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active properties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the surfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients

Background Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. Patients and methods Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). Results A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). Conclusion High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimen

The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease

UNLABELLED BACKGROUND Chemokine receptor CXCR4, together with its ligand CXCL12, plays critical roles in cancer progression, including growth, metastasis and angiogenesis. Ewing sarcoma is a sarcoma with poor prognosis despite current therapies, particularly for patients with advanced-stage disease. Lungs and bone (marrow), organs of predilection for (primary/metastatic) Ewing sarcoma, represent predominant CXCL12 sources. METHODS To gain insight into the role of the CXCR4-CXCL12 axis in Ewing sarcoma, CXCR4, CXCL12 and hypoxia-inducible factor-1α protein expression was studied in therapy-naïve and metastatic tumors by immunohistochemistry. CXCR4 function was assessed in vitro, by flow cytometry and proliferation/ cell viability assays, in the presence of recombinant CXCL12 and/or CXCR4-antagonist AMD3100 or under hypoxic conditions. RESULTS Whereas CXCR4 was predominantly expressed by tumor cells, CXCL12 was observed in both tumor and stromal areas. Survival analysis revealed an (expression level-dependent) negative impact of CXCR4 expression (p < 0.04). A role for the CXCR4-CXCL12 axis in Ewing sarcoma growth was suggested by our observations that i) CXCR4 expression correlated positively with tumor volume at diagnosis (p = 0.013), ii) CXCL12 was present within the microenvironment of virtually all cases, iii) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines, which could be abrogated by AMD3100. CXCR4 expression was not correlated with occurrence of metastatic disease. Also, therapy-naïve tumors demonstrated higher CXCR4 expression as compared to metastases (p = 0.027). Evaluation of in vivo hypoxia-inducible factor-1α expression and culture of cells under hypoxic conditions revealed no role for hypoxia in CXCR4 expression. CONCLUSIONS Together, our results imply a crucial role for the CXCR4-CXCL12 axis in auto- and/or paracrine growth stimulation. Integration of CXCR4-targeting strategies into first- and/or second-line treatment regimens may represent a promising treatment option for Ewing sarcoma.Molecular tumour pathology - and tumour genetic

Short-term variability of biomarkers of proteinase activity in patients with emphysema associated with type Z alpha-1-antitrypsin deficiency

BACKGROUND: The burden of proteinases from inflammatory cells in the lung of subjects with type Pi ZZ of alpha-1-antitrypsin deficiency is higher than in those without the deficiency. Cross-sectional studies have shown increased levels of biomarkers of extracellular matrix degradation in vivo. Longitudinal variability of these biomarkers is unknown but desirable for clinical studies with proteinase inhibitors. METHODS: We measured three different types of biomarkers, including desmosines, elastase-formed fibrinogen fragments and heparan sulfate epitope JM403, in plasma and urine for a period of 7 weeks in a group of 12 patients who participated in a placebo-controlled study to assess the safety of a single inhalation of hyaluronic acid. RESULTS: Effect of study medication on any of the biomarkers was not seen. Baseline desmosines in plasma and urine correlated with baseline CO diffusion capacity (R = 0.81, p = 0.01 and R = 0.65, p = 0.05). Mean coefficient of variation within patients (CVi) for plasma and urine desmosines was 18.7 to 13.5%, respectively. Change in urinary desmosine levels correlated significantly with change in plasma desmosine levels (R = 0.84, p < 0.01). Mean CVi for fibrinogen fragments in plasma was 20.5% and for JM403 in urine was 27.8%. No correlations were found between fibrinogen fragments or JM403 epitope and desmosines. CONCLUSION: We found acceptable variability in our study parameters, indicating the feasibility of their use in an evaluation of biochemical efficacy of alpha-1-antitrypsin augmentation therapy in Pi Z subjects

High specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG positive Ewing sarcoma

Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available

What contributes to patient and parent satisfaction with medication in the treatment of children with ADHD? A report on the development of a new rating scale

Satisfaction with medication is important in the evaluation of overall treatment outcome. There is a lack of consistent and validated rating scales for satisfaction with medication in ADHD, therefore comparison across studies is difficult. Here, we analyse the psychometric properties of the satisfaction with medication scale (SAMS), a new item-based questionnaire that assesses satisfaction with ADHD medication. Furthermore, we evaluate the predictive effect of ADHD symptoms and quality of life (QoL) on satisfaction. Data on satisfaction with Equasym XL® (methylphenidate) were collected in the OBSEER study using the parent (SAMS-P, n = 589) and patient (SAMS-S, n = 552) versions of the SAMS questionnaire. Internal consistency, item-total and cross-informant correlations, and the stability of satisfaction ratings over time were assessed. Satisfaction with medication scores were then correlated with ratings of ADHD symptoms and QoL. Rates of overall satisfaction with Equasym XL® among parents and children were high (>70%), as was internal consistency for both SAMS-P and SAMS-S (Cronbach’s alpha > 0.9). Similarly, item-total correlations were high (r = 0.71–0.90) for SAMS-P and medium–high (r = 0.57–0.77) for SAMS-S. Cross-informant correlations and the stability of satisfaction ratings were moderate (r = 0.54–0.59 and 0.48–0.60, respectively). ADHD symptom and QoL ratings were significantly negative and positive predictors of satisfaction, explaining 36–52% of satisfaction variance at the final visit. The results show that parent and patient satisfaction was high and could be assessed reliably with the new SAMS questionnaire. Parent and patient ratings were moderately correlated, and symptom severity, functional impairment and QoL were the most significant predictors of satisfaction

The receptor tyrosine kinase RON and its isoforms as therapeutic targets in Ewing sarcoma

Animal science