Long-term persistence in patients with osteoporosis receiving denosumab in routine practice: 36-month non-interventional, observational study.

Persistence rates over 36 months with denosumab in patients diagnosed with osteoporosis in a real-world setting were examined, along with baseline patient characteristics predictive of persistence. This study represents the longest observational period with denosumab persistence and shows higher persistence rates when compared to bisphosphonates. INTRODUCTION: The study objective was to describe long-term persistence with denosumab among patients treated for osteoporosis in a real-world setting. We also sought to examine patient characteristics predictive of persistence. Lastly, this study attempted to place the results in context by conducting a literature review of published persistence data for denosumab. METHODS: This retrospective, non-interventional study analyzed 1158 patients from a specialty community private practice to assess patient persistence with denosumab in routine care. Persistence was defined as receiving seven denosumab injections, using an 8-week permissible gap, over 36 months. Non-persistent patients were further investigated retrospectively to identify reasons for discontinuation, when available. RESULTS: Demographic analysis showed a population of 1158 patients with mean age 68.4 years old and baseline T-score - 2.7; nearly half of which experienced a prior osteoporosis-related fracture. In a Kaplan-Meier survival analysis, 36-month persistence overall was 50.7%. Net persistence, as defined by receiving seven injections in the allowable time frame, was 64.2% of the cohort. In a multivariate analysis, prior vertebral fractures and recent osteoporosis therapy were associated with higher persistence; age greater than 75 years was associated with non-persistence. Reasons for discontinuation were available in 91.6% of non-persistent patients and categorized to include the ten most common explanations. CONCLUSION: This study to our knowledge represents the longest continuous observational period providing data on denosumab persistence in a real-world setting. The total persistence noted is quite robust when compared to bisphosphonates and is within the upper range of prior published studies of denosumab with shorter observation periods.

Light echoes reveal an unexpectedly cool η Carinae during its nineteenth-century Great Eruption.

η Carinae is one of the most massive binary stars in the Milky Way. It became the second-brightest star in our sky during its mid-nineteenth-century 'Great Eruption', but then faded from view (with only naked-eye estimates of brightness). Its eruption is unique in that it exceeded the Eddington luminosity limit for ten years. Because it is only 2.3 kiloparsecs away, spatially resolved studies of the nebula have constrained the ejected mass and velocity, indicating that during its nineteenth-century eruption, η Car ejected more than ten solar masses in an event that released ten per cent of the energy of a typical core-collapse supernova, without destroying the star. Here we report observations of light echoes of η Carinae from the 1838-1858 Great Eruption. Spectra of these light echoes show only absorption lines, which are blueshifted by -210 km s(-1), in good agreement with predicted expansion speeds. The light-echo spectra correlate best with those of G2-to-G5 supergiants, which have effective temperatures of around 5,000 kelvin. In contrast to the class of extragalactic outbursts assumed to be analogues of the Great Eruption of η Carinae, the effective temperature of its outburst is significantly lower than that allowed by standard opaque wind models. This indicates that other physical mechanisms such as an energetic blast wave may have triggered and influenced the eruption.

Sonic hedgehog gene therapy increases the ability of the dystrophic skeletal muscle to regenerate after injury.

The Hedgehog (Hh) pathway is a crucial regulator of muscle development during embryogenesis. We have previously demonstrated that Sonic hedgehog (Shh) regulates postnatal myogenesis in the adult skeletal muscle both directly, by acting on muscle satellite cells, and indirectly, by promoting the production of growth factors from interstitial fibroblasts. Here, we show that in mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, progression of the dystrophic pathology corresponds to progressive inhibition of the Hh signaling pathway in the skeletal muscle. We also show that the upregulation of the Hh pathway in response to injury and during regeneration is significantly impaired in mdx muscle. Shh treatment increases the proliferative potential of satellite cells isolated from the muscles of mdx mice. This treatment also increases the production of proregenerative factors, such as insulin-like growth factor-1 and vascular endothelial growth factor, from fibroblasts isolated from the muscle of mdx mice. In vivo, overexpression of the Hh pathway using a plasmid encoding the human Shh gene promotes successful regeneration after injury in terms of increased number of proliferating myogenic cells and newly formed myofibers, as well as enhanced vascularization and decreased fibrosis.

Toward the identification of peripheral epigenetic biomarkers of schizophrenia.

Schizophrenia (SZ) is a heritable, nonmendelian, neurodevelopmental disorder in which epigenetic dysregulation of the brain genome plays a fundamental role in mediating the clinical manifestations and course of the disease. The authors recently reported that two enzymes that belong to the dynamic DNA methylation/demethylation network-DNMT (DNA methyltransferase) and TET (ten-eleven translocase; 5-hydroxycytosine translocator)-are abnormally increased in corticolimbic structures of SZ postmortem brain, suggesting a causal relationship between clinical manifestations of SZ and changes in DNA methylation and in the expression of SZ candidate genes (e.g., brain-derived neurotrophic factor [BDNF], glucocorticoid receptor [GCR], glutamic acid decarboxylase 67 [GAD67], reelin). Because the clinical manifestations of SZ typically begin with a prodrome followed by a first episode in adolescence with subsequent deterioration, it is obvious that the natural history of this disease cannot be studied only in postmortem brain. Hence, the focus is currently shifting towards the feasibility of studying epigenetic molecular signatures of SZ in blood cells. Initial studies show a significant enrichment of epigenetic changes in lymphocytes in gene networks directly relevant to psychiatric disorders. Furthermore, the expression of DNA-methylating/demethylating enzymes and SZ candidate genes such as BDNF and GCR are altered in the same direction in both brain and blood lymphocytes. The coincidence of these changes in lymphocytes and brain supports the hypothesis that common environmental or genetic risk factors are operative in altering the epigenetic components involved in orchestrating transcription of specific genes in brain and peripheral tissues. The identification of DNA methylation signatures for SZ in peripheral blood cells of subjects with genetic and clinical high risk would clearly have potential for the diagnosis of SZ early in its course and would be invaluable for initiating early intervention and individualized treatment plans.

Serum apolipoprotein C-II is prognostic for survival after pancreatic resection for adenocarcinoma.

BACKGROUND: Pancreaticoduodenectomy remains a major undertaking. A preoperative blood test, which could confidently predict the benefits of surgery would improve the selection of pancreatic cancer patients for surgery. This study aimed to identify protein biomarkers prognostic for long-term survival and to validate them with clinico-pathological information. METHODS: Serum from 40 preoperative patients was used to train for predictive biomarkers using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI), and the results were verified on 21 independent samples. Two predictive proteins were identified by tryptic peptide mass fingerprinting and sequencing, and validated on serum from another 57 patients by enzyme-linked immunosorbent assay (ELISA). The influence of these proteins on growth and invasion of two cancer cell lines was tested in-vitro. RESULTS: The SELDI panel of m/z 3700, 8222 and 11 522 peaks predicted <12 months' survival (ROC AUC: 0.79, 0.64-0.90; P<0.039). When CA19-9 was added, the ROC AUC increased to 0.95 (0.84-0.99; P<0.0001). The six subjects in the verification group who died within 12 months were correctly classified. The m/z 8222 and 11 522 proteins were identified as Serum ApoC-II and SAA-1, respectively. In the validation samples, ELISA results confirmed that ApoC-II was predictive of survival (Kaplan-Meier P<0.009), but not SAA-I. ApoC-II, CA19-9 and major-vessel involvement independently predicted survival. ApoC-II and SAA-1 increased cell growth and invasion of both cancer cell lines. CONCLUSION: Serum ApoC-II, CA19-9 and major-vessel invasion independently predict survival and improves selection of patients for pancreaticoduodenectomy.

Direct measurement of bend-induced mode deformation in large-mode-area fibers.

In 1976 Marcuse developed an equivalent index model to predict the effects of bending in waveguides, and predicted deformation of the spatial modes in bent optical fibers. Perturbative approaches have been previously applied and tested to predict the behavior of single- and few-moded-fibers. However, much more significant mode deformation has been predicted for large-mode-area fibers than for single- or few-moded-fibers. In this paper, the spatial profiles of modes deformed by bending in large-mode-area fibers are measured for the first time. A finite difference method employing the equivalent index model is used to calculate the modes of the helical fiber, which show an offset that is twice as large as that predicted for single-mode fiber, and mode compression that is five times greater. These calculated results are compared to the experimental data, yielding significantly better agreement than previous perturbative approaches.

Residential Homes with Extremely High Indoor Radon Concentrations in Southern Lehigh County, Pennsylvania.

ABSTRACT: A housing development of 87 new homes on approximately 300 acres of former farm land was found to have 19 homes with basement radon-222 ( 222 Rn) concentrations greater than 37,000 Bq m -3 , with the highest recorded result to date being 648,000 +/- 1,031 Bq m -3 , based upon the diffusion barrier charcoal canister result. The US Environmental Protection Agency (EPA) Action Level for 222 Rn is 148 Bq m -3 . This single-family housing development is in the southeast corner of Lehigh County, Pennsylvania, about 58 km northwest of Philadelphia, in a geologic unit known as the Epler Formation. Radon testing in homes in this development began in the fall of 2014 and is now complete. Initial testing consisted of charcoal canisters mailed to homeowners. Subsequent testing in newly built homes consisted of testing prior to occupancy. This testing was quite extensive, with continuous radon monitors, passive radon monitors, and grab sampling for radon gas and progeny in the basement and on the first floor of each home as well as gamma surveys in the basement, on the first and second floors, and outside of each home. All but one of the new houses in this development had passive radon resistant features installed during the construction phase. In all cases, fans were added to the passive systems to make them active systems, which were needed to control these extremely high radon levels. Additional radon mitigation work such as adding additional suction points was also needed in several homes to reduce levels to below EPA guidelines. The unique geology and high 226 Ra soil concentrations in this specific area are the causes of these extremely high radon levels. Radon measurement data both inside these homes and in the outdoor ambient air, as well as 238 U and 222 Ra rock and soil concentrations, are presented.

A combination of serum leucine-rich α-2-glycoprotein 1, CA19-9 and interleukin-6 differentiate biliary tract cancer from benign biliary strictures.

BACKGROUND: Biliary tract cancer (BTC) and benign biliary strictures can be difficult to differentiate using standard tumour markers such as serum carbohydrate antigen 19-9 (CA19-9) as they lack diagnostic accuracy. METHODS: Two-dimensional difference gel electrophoresis and tandem mass spectrometry were used to profile immunodepleted serum samples collected from cases of BTC, primary sclerosing cholangitis (PSC), immunoglobulin G4-associated cholangitis and healthy volunteers. The serum levels of one candidate protein, leucine-rich α-2-glycoprotein (LRG1), were verified in individual samples using enzyme-linked immunosorbent assay and compared with serum levels of CA19-9, bilirubin, interleukin-6 (IL-6) and other inflammatory markers. RESULTS: We report increased LRG1, CA19-9 and IL-6 levels in serum from patients with BTC compared with benign disease and healthy controls. Immunohistochemical analysis also demonstrated increased staining of LRG1 in BTC compared with cholangiocytes in benign biliary disease. The combination of receiver operating characteristic (ROC) curves for LRG1, CA19-9 and IL-6 demonstrated an area under the ROC curve of 0.98. In addition, raised LRG1 and CA19-9 were found to be independent predictors of BTC in the presence of elevated bilirubin, C-reactive protein and alkaline phosphatase. CONCLUSION: These results suggest LRG1, CA19-9 and IL-6 as useful markers for the diagnosis of BTC, particularly in high-risk patients with PSC.

Identification of an endogenous inhibitor of prostatic carcinoma cell growth.

The rate of expansion of primary prostatic carcinoma is comparatively slow, with tumours frequently taking years or decades to reach clinically relevant size. We now report the presence of an endogenous inhibitor, derived from aqueous extracts of human prostate tissue, which blocks prostatic carcinoma cell proliferation in vitro and prevents subcutaneous tumour expansion in vivo. Purification and characterization revealed the inhibitor to be spermine, a polyamine known to be locally abundant in the prostate. These results suggest that endogenous polyamine can negatively regulate the growth of prostatic carcinoma cells at their primary site in vivo and may explain the slow rate of primary tumour expansion in the prostate.

Discovery of serum biomarkers for pancreatic adenocarcinoma using proteomic analysis.

BACKGROUND AND AIMS: The serum/plasma proteome was explored for biomarkers to improve the diagnostic ability of CA19-9 in pancreatic adenocarcinoma (PC). METHODS: A Training Set of serum samples from 20 resectable and 18 stage IV PC patients, 54 disease controls (DCs) and 68 healthy volunteers (HVs) were analysed by surface-enhanced laser desorption and ionisation time-of-flight mass spectrometry (SELDI-TOF MS). The resulting protein panel was validated on 40 resectable PC, 21 DC and 19 HV plasma samples (Validation-1 Set) and further by ELISA on 33 resectable PC, 28 DC and 18 HV serum samples (Validation-2 Set). Diagnostic panels were derived using binary logistic regression incorporating internal cross-validation followed by receiver operating characteristic (ROC) analysis. RESULTS: A seven-protein panel from the training set PC vs DC and from PC vs HV samples gave the ROC area under the curve (AUC) of 0.90 and 0.90 compared with 0.87 and 0.91 for CA19-9. The AUC was greater (0.97 and 0.99, P<0.05) when CA19-9 was added to the panels and confirmed on the validation-1 samples. A simplified panel of apolipoprotein C-I (ApoC-I), apolipoprotein A-II (ApoA-II) and CA19-9 was tested on the validation-2 set by ELISA, in which the ROC AUC was greater than that of CA19-9 alone for PC vs DC (0.90 vs 0.84) and for PC vs HV (0.96 vs 0.90). CONCLUSIONS: A simplified diagnostic panel of CA19-9, ApoC-I and ApoA-II improves the diagnostic ability of CA19-9 alone and may have clinical utility.

Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3'-untranslated region.

RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10-0.54, P=0.001) in the overall sample, and 0.20 (0.07-0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11-0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3'-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression.

Stratospheric ozone, middle ultraviolet radiation, and carbon-14 measurements of marine productivity.

The effects of increased ultraviolet radiation, due to decreased stratospheric ozone, on marine phytoplankton have been investigated with the use of static bottle in situ carbon-14 productivity measurements. The relative biological efficiency for photoinhibition may be used to calculate biologically effective doses and resultant amplification factors. The carbon-14 technique (short-term incubations) is inadequate for assessment of possible large amplification factor photoprocesses that may be ecologically significant.

Drift of continental rafts with asymmetric heating.

A laboratory model of a lithospheric raft is propelled through a viscous asthenospheric layer with constant velocity of scaled magnitude appropriate to continental drift. The propulsion is due to differential heat concentration in the model oceanic and continental crusts.

Schizophrenic symptoms improve with apomorphine.

Eighteen chronic schizophrenic patients received subcutaneous doses of apomorphine, a dopamine receptor agonist, and of placebo in separate trials. A significant improvement in psychotic symptoms occurred after apomorphine compared to placebo. The results are interpreted as a consequence of presynaptic dopamine receptor activation by apomorphine with a subsequent decrease in dopamine-mediated neural transmission.

Phytoplankton blooming off the u.s. East coast: a satellite description.

A "bloom" of near-surface phytoplankton occurs in the Atlantic Slope region of the western Atlantic Ocean off the U.S. East Coast in the spring. Satellite time series of sea-surface temperature and phytoplankton pigment concentration, derived from measurements of the National Oceanic and Atmospheric Administration NOAA-7 Advanced Very-High-Resolution Radiometer and the National Aeronautics and Space Administration Nimbus-7 Coastal Zone Color Scanner, respectively, give information on the spatial extent and temporal development of such a bloom for a 28-day period in April through May 1982. The phytoplankton concentration of the slope area is comparable to that of the Atlantic Shelf. Total primary productivity of the slope during this period is equivalent to that of the shelf. The primary productivity within a warm-core ring and in the Gulf Stream system is less by a factor of 2.

Ozone depletion: ultraviolet radiation and phytoplankton biology in antarctic waters.

The springtime stratospheric ozone (O3) layer over the Antarctic is thinning by as much as 50 percent, resulting in increased midultraviolet (UVB) radiation reaching the surface of the Southern Ocean. There is concern that phytoplankton communities confined to near-surface waters of the marginal ice zone will be harmed by increased UVB irradiance penetrating the ocean surface, thereby altering the dynamics of Antarctic marine ecosystems. Results from a 6-week cruise (Icecolors) in the marginal ice zone of the Bellingshausen Sea in austral spring of 1990 indicated that as the O3 layer thinned: (i) sea surface- and depth-dependent ratios of UVB irradiance (280 to 320 nanometers) to total irradiance (280 to 700 nanometers) increased and (ii) UVB inhibition of photosynthesis increased. These and other Icecolors findings suggest that O3-dependent shifts of in-water spectral irradiances alter the balance of spectrally dependent phytoplankton processes, including photoinhibition, photoreactivation, photoprotection, and photosynthesis. A minimum 6 to 12 percent reduction in primary production associated with O3 depletion was estimated for the duration of the cruise.

Electron transfer from a carbon nanotube into vacuum under high electric fields.

The transfer of an electron from a carbon nanotube (CNT) tip into vacuum under a high electric field is considered beyond the usual one-dimensional semi-classical approach. A model of the potential energy outside the CNT cap is proposed in order to show the importance of the intrinsic CNT parameters such as radius, length and vacuum barrier height. This model also takes into account set-up parameters such as the shape of the anode and the anode-to-cathode distance, which are generically portable to any modelling study of electron emission from a tip emitter. Results obtained within our model compare well to experimental data. Moreover, in contrast to the usual one-dimensional Wentzel-Kramers-Brillouin description, our model retains the ability to explain non-standard features of the process of electron field emission from CNTs that arise as a result of the quantum behaviour of electrons on the surface of the CNT.

Respirometric evaluation of side-stream treatment of reject water as a source of nitrifying bacteria for main-stream activated sludge bioreactors.

A laboratory-scale bioreactor study was conducted to characterize differences in nitrification function in main-stream reactors due to bioaugmentation from side-stream reactors treating reject water. The objective was to evaluate how configuration of a suspended growth side-stream bioreactor impacts nitrification function in the main-stream bioreactor. A bioaugmentation effect was not observed in main-stream reactors operated at warm temperatures. Complete oxidation of ammonia to nitrate was observed in the bioaugmented and control main-stream reactors although nitrite accumulation was observed in each case. Furthermore, respirometry did not reveal superior kinetics in bioaugmented reactors operated at warm temperatures. At cold temperatures bioaugmentation may have stabilized ammonia oxidation in main-stream reactor B2 bioaugmented from a PFR side-stream. Complete ammonia oxidation was observed for most of cold period of operation in the main-stream bioreactor B2. Furthermore, respirometry revealed a higher rate of ammonia oxidation and more stable nitrite oxidation compared with the control bioreactor.

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia.

Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.

Ecological engineering of bioaugmentation from side-stream nitrification.

Wastewater treatment relies on careful integration of environmental engineering with microbial ecology. This would seem to be particularly the case when attempting to enhance survivability of organisms introduced from outside the main-stream reactor, i.e. bioaugmentation. Molecular biology tools were utilised in this study to assist in understanding the mechanisms of successful bioaugmentation. Molecular fingerprinting showed that side-stream reactor configuration strongly influenced ammonia-oxidising bacteria (AOB) community structure. In both lab-scale and full-scale systems, AOB communities in the side-stream and main-stream were very similar. The experimental systems revealed that a PFR side-stream produced greater diversity of AOB than a CSTR side-stream in a PFR main-stream system, whereas the full-scale side-stream resulted in essentially an AOB monoculture. Phylogenetic analysis revealed less diversity than molecular fingerprinting perhaps due to biases in the cloning/transformation procedure.