Cretaceous age, composition, and microstructure of pseudotachylyte in the Otago Schist, New Zealand

At Tucker Hill, in Central Otago, New Zealand, a series of pseudotachylyte veins are hosted in quartzofeldspathic schist. Chilled margins, microlites, flow banding, and the crystallisation of mineral phases absent from the host rock provide unequivocal evidence for melting during pseudotachylyte formation. Whole rock analyses of pseudotachylyte reveal c. 3 enrichment of K2O, Ba, and Rb, and similar depletion of Na2O, CaO, Sr, and Eu, as compared to host schist. Formation age of pseudotachylyte is 95.9±1.8 Ma as measured by total fusion 40Ar/39Ar analyses. Stepwise heating of pseudotachylyte matrix yields an excellently defined 40Ar/39Ar plateau age of 96.0±0.3 Ma. These well-defined ages are attributed to the presence of potassium feldspar, low abundance of inherited lithic material from the host rock, and few fluid inclusions containing extraneous Ar. We propose that formation of these pseudotachylyte veins was related to Cretaceous extensional uplift and exhumation of the Otago Schist

Identifying Individuals at Risk for Fracture in Guatemala

INTRODUCTION: The FRAX calculator combines a set of clinical risk factors with country-specific incidence rates to determine the ten-year absolute risk of major osteoporotic fracture. However, regional or country-specific databases from Central American countries are not available. We compared the use of various FRAX databases and the Pluijm algorithm in determining risk of fracture. METHODS: We collected clinical risk factor data needed for the FRAX calculator and Pluijm algorithm of Hispanic women in Guatemala and calculated the FRAX absolute risk measures of major osteoporotic fracture and hip fracture. Subjects were postmenopausal women greater than age 40 with no history of using medication that affect bone. A random sample of 204 women in 34 different regions women in Guatemala City was visited in their homes to complete the surveys. The Pluijm risk score and FRAX risk score using the US Hispanic, Spain, and Mexican databases were calculated. RESULTS: We used the US NOF guidelines for treatment which suggest a treatment threshold for patients with a 10-year hip fracture probability ≥ 3% or a 10-year major osteoporotic fracture risk ≥ 20%. The number of patients meeting the suggested threshold limits for treatment using the Spain and Mexico calculators were identical. There was 100% conformity in threshold limits for both hip and major osteoporotic fracture risk. The mean conformity for any fracture risk between US Hispanic and the other two databases was 97.5%. Conformity was 99.0% based on major osteoporotic fracture and 97.5% based on risk of hip fracture. The Pluijm evaluation shows conformity of 87.2% and 83.3%, respectively, when compared to the US Hispanic and Spain/Mexico FRAX thresholds for risk of fracture. DISCUSSION: Although the different FRAX databases provide variations in the absolute risk of fracture, the overall conformity to treatment thresholds amongst the US Hispanic, Spain, and Mexico databases show the database used would have little effect as to the decision to treat. The Pluijm tool conforms to the FRAX thresholds and can be used as well. It does not matter which country-specific calculator or assessment tool is used, as there are a similar number of patients that would meet the intervention threshold

Molecular alterations that drive breast cancer metastasis to bone.

Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis

Discordant Silurian paleolatitudes for central Newfoundland: New paleomagnetic evidence from the Springdale Group

Ancient remanences are retained by the Early Silurian (429 + 6/-5 Ma) mafic volcanics of the Springdale Caldera (five sites) and the overlying red beds (seven sites). Dual polarity magnetizations are obtained by thermal demagnetization of samples from the red beds, whereas single polarity directions are observed in the volcanics. High unblocking temperatures indicate hematite as the remanence carrier in both the volcanics and sediments. These high-temperature, characteristic remanences are easily isolated and pass both the tilt and conglomerate tests; they are likely to be of primary Silurian age. Characteristic declinations are predominantly northerly and northeasterly, and indicate significant structural rotations on a local scale. When the results of the red beds and the volcanics are combined they show characteristic inclinations that are shallower than those of the correlative Botwood Group (ca. 36[deg] vs. 43[deg]) but not nearly as shallow as those reported from the King George IV Lake area (0.5[deg]). Mean inclinations obtained from the Springdale red beds are, however, significantly shallower than those of the Springdale volcanics. The same difference can be seen in other previous Silurian paleomagnetic studies of central Newfoundland. We infer that an inclination error affects the red bed magnetizations of the Springdale Group, Botwood Group (Wigwam Formation) and rocks of the King George IV Lake area. Therefore, the results from Silurian red beds should not be used to determine paleolatitudes for central Newfoundland. The mean paleolatitude of the Springdale Group volcanics is 30[deg]. The mean paleolatitudes for both the Springdale volcanics and Botwood volcanics (Lawrenceton Formation) are indistinguishable within paleomagnetic error limits from the predicted paleolatitude of Newfoundland on the northeast-trending North American margin. Thus, no detectable post-Silurian displacement is shown by the volcanics of the Springdale Group with respect to cratonic North America.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30456/1/0000084.pd

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.British Journal of Cancer advance online publication, 22 December 2016; doi:10.1038/bjc.2016.402 www.bjcancer.com

A classification tree for predicting recurrent falling in community-dwelling older persons

OBJECTIVES: To develop a classification tree for predicting the risk of recurrent falling in community-dwelling older persons using tree-structured survival analysis (TSSA). DESIGN: A prospective cohort study. SETTING: A community in the Netherlands. PARTICIPANTS: One thousand three hundred sixty-five community-dwelling older persons (≥65) from the Longitudinal Aging Study Amsterdam (LASA). MEASUREMENTS: In 1995, physical, cognitive, emotional, and social aspects of functioning were assessed. Subsequently, a prospective fall follow-up, specifically on recurrent falls (two falls within 6 months) was conducted for 3 years. RESULTS: The classification tree included 11 end groups differing in risk of recurrent falling based on a minimum of two and a maximum of six predictors. The first split in the tree involved two or more falls versus fewer than two falls in the year preceding the interview. Respondents with two or more falls in the year preceding the interview (n = 193) and with at least two functional limitations (n = 98) had a 75% risk of becoming a recurrent faller, whereas respondents with fewer than two functional limitations were further divided into a group with regular dizziness (n = 11, risk of 68%) and a group with no regular dizziness (n = 84, risk of 30%). In respondents with fewer than two falls in the year preceding the interview (n = 1, 172), the risk of becoming a recurrent faller varied between 9% and 70%. Predictors in this branch of the tree were low performance, low handgrip strength, alcohol use, pain, high level of education, and high level of physical activity. CONCLUSION: This classification tree included 11 end groups differing in the risk of recurrent falling based on specific combinations of a maximum of six easily measurable predictors. The classification tree can identify subjects who are eligible for preventive measures in public health strategies

A risk profile for identifying community-dwelling elderly with a highrisk of recurrent falling: results of a 3-year prospective study

Introduction: The aim of the prospective study reported here was to develop a risk profile that can be used to identify community-dwelling elderly at a high risk of recurrent falling. Materials and methods: The study was designed as a 3-year prospective cohort study. A total of 1365 community-dwelling persons, aged 65 years and older, of the population-based Longitudinal Aging Study Amsterdam participated in the study. During an interview in 1995/1996, physical, cognitive, emotional and social aspects of functioning were assessed. A follow-up on the number of falls and fractures was conducted during a 3-year period using fall calendars that participants filled out weekly. Recurrent fallers were identified as those who fell at least twice within a 6-month period during the 3-year follow-up. Results: The incidence of recurrent falls at the 3-year follow-up point was 24.9% in women and 24.4% in men. Of the respondents, 5.5% reported a total of 87 fractures that resulted from a fall, including 20 hip fractures, 21 wrist fractures and seven humerus fractures. Recurrent fallers were more prone to have a fall-related fracture than those who were not defined as recurrent fallers (11.9% vs. 3.4%; OR: 3.8; 95% CI: 2.3-6.1). Backward logistic regression analysis identified the following predictors in the risk profile for recurrent falling: two or more previous falls, dizziness, functional limitations, weak grip strength, low body weight, fear of falling, the presence of dogs/cats in the household, a high educational level, drinking 18 or more alcoholic consumptions per week and two interaction terms (high educationx18 or more alcohol consumptions per week and two or more previous falls x fear of falling) (AUC=0.71). Discussion: At a cut-off point of 5 on the total risk score (range 0-30), the model predicted recurrent falling with a sensitivity of 59% and a specificity of 71%. At a cut-off point of 10, the sensitivity and specificity were 31% and 92%, respectively. A risk profile including nine predictors that can easily be assessed seems to be a useful tool for the identification of community-dwelling elderly with a high risk of recurrent falling. © International Osteoporosis Foundation and National Osteoporosis Foundation 2006

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels 50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715.Prostatic carcinom

Ercc1 DNA repair deficiency results in vascular aging characterized by VSMC phenotype switching, ECM remodeling, and an increased stress response

Cardiovascular diseases are the number one cause of death globally. The most important determinant of cardiovascular health is a person's age. Aging results in structural changes and functional decline of the cardiovascular system. DNA damage is an important contributor to the aging process, and mice with a DNA repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, and loss of vasomotor control. To determine the underlying cause, we compared important hallmarks of vascular aging in aortas of both Ercc1Δ/− and age-matched wildtype mice. Additionally, we investigated vascular aging in 104 week old wildtype mice. Ercc1Δ/− aortas displayed arterial thickening, a loss of cells, and a discontinuous endothelial layer. Aortas of 24 week old Ercc1Δ/− mice showed phenotypical switching of vascular smooth muscle cells (VSMCs), characterized by a decrease in contractile markers and a decrease in synthetic markers at the RNA level. As well as an increase in osteogenic markers, microcalcification, and an increase in markers for damage induced stress response. This suggests that Ercc1Δ/− VSMCs undergo a stress-induced contractile-to-osteogenic phenotype switch. Ercc1Δ/− aortas showed increased MMP activity, elastin fragmentation, and proteoglycan deposition, characteristic of vascular aging and indicative of age-related extracellular matrix remodeling. The 104 week old WT mice showed loss of cells, VSMC dedifferentiation, and senescence. In conclusion, Ercc1Δ/− aortas rapidly display many characteristics of vascular aging, and thus the Ercc1Δ/− mouse is an excellent model to evaluate drugs that prevent vascular aging in a short time span at the functional, histological, and cellular level.</p

Ercc1 DNA repair deficiency results in vascular aging characterized by VSMC phenotype switching, ECM remodeling, and an increased stress response

Cardiovascular diseases are the number one cause of death globally. The most important determinant of cardiovascular health is a person's age. Aging results in structural changes and functional decline of the cardiovascular system. DNA damage is an important contributor to the aging process, and mice with a DNA repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, and loss of vasomotor control. To determine the underlying cause, we compared important hallmarks of vascular aging in aortas of both Ercc1Δ/− and age-matched wildtype mice. Additionally, we investigated vascular aging in 104 week old wildtype mice. Ercc1Δ/− aortas displayed arterial thickening, a loss of cells, and a discontinuous endothelial layer. Aortas of 24 week old Ercc1Δ/− mice showed phenotypical switching of vascular smooth muscle cells (VSMCs), characterized by a decrease in contractile markers and a decrease in synthetic markers at the RNA level. As well as an increase in osteogenic markers, microcalcification, and an increase in markers for damage induced stress response. This suggests that Ercc1Δ/− VSMCs undergo a stress-induced contractile-to-osteogenic phenotype switch. Ercc1Δ/− aortas showed increased MMP activity, elastin fragmentation, and proteoglycan deposition, characteristic of vascular aging and indicative of age-related extracellular matrix remodeling. The 104 week old WT mice showed loss of cells, VSMC dedifferentiation, and senescence. In conclusion, Ercc1Δ/− aortas rapidly display many characteristics of vascular aging, and thus the Ercc1Δ/− mouse is an excellent model to evaluate drugs that prevent vascular aging in a short time span at the functional, histological, and cellular level.</p