Atypical teratoid rhabdoid tumours (ATRTs)-a 21-year institutional experience.

PURPOSE: Atypical teratoid/rhabdoid tumours (ATRTs) are malignant embryonal tumours of childhood that affect the central nervous system (CNS). We aim to determine which factors, including patient age, extent of resection (EOR), presence of distal metastasis and use of adjuvant therapies, affect overall survival in children with atypical teratoid/rhabdoid tumours (ATRTs) treated at this single centre. METHODS: Retrospective cohort review of patients with histological diagnosis of ATRT treated over 21 years (1999-2020) was conducted. Data on demographics, tumour location, presence of metastasis, use of adjuvant therapy, extent of resection (EOR), complications, neurological outcome post-surgery, and overall survival were collected. Kaplan-Meier survival analysis was performed. RESULTS: A total of 45 children (mean age 2 years) underwent 64 operations. 25 patients were <1 year of age. Gross-total resection (GTR) pre-adjuvant therapy was achieved in 15, near-total resection (NTR) in 15, subtotal resection (STR) in 9, and biopsy in 6 children. Most children had good neurological outcomes post-operatively (28/45 with GOS 5). Fourteen patients survived longer than 4 years. Survival analysis showed a significant difference in median survival in favour of GTR and localised disease. There was no significant difference in median survival between patients <1 year vs >1 year of age (p=0.84). CONCLUSION: We find that presence of metastasis was an important factor in poor survival in patients with ATRT. GTR, where possible, may confer significant survival benefit in ATRT. Children aged <1 year appear to have performed as well as those >1 year and therefore should still be considered for radical surgery.

Visual outcomes and predictors in optic pathway glioma: a single centre study.

BACKGROUND/AIMS: Optic pathway gliomas (OPGs) may cause progressive visual loss despite chemotherapy. Newer, less toxic treatments might be given earlier, depending on visual prognosis. We aimed to investigate the prognostic value of visual evoked potentials (VEP) and optical coherence tomography (OCT). METHODS: A retrospective study of OPG patients (treated 2003-2017) was conducted. Primary outcome was PEDIG category visual acuity in better and worse eyes (good < = 0.2, moderate 0.3-0.6 and poor > = 0.7 logMAR). Binary logistic regression analysis was used to identify predictors of these outcomes. RESULTS: 60 patients (32 Neurofibromatosis type 1 [NF1] and 28 sporadic) had median presentation age 49 months (range 17-183) (NF1) and 27 months (range 4-92) (sporadic). Median follow up was 82 months (range 12-189 months). At follow up 24/32 (75%) of NF1 children and 14/28 (50%) of sporadic children had good better eye visual acuity and 11/32 (34%) of NF1 children and 15/28 (54%) of sporadics had poor worse eye acuity. Mean peripapillary retinal nerve fibre layer (RNFL) thickness predicted good better eye final acuity (OR 0.799, 95%CI 0.646-0.987, p = 0.038). Presenting with visual symptoms (OR 0.22 95% CI 0.001-0.508, p = 0.017) and poorer VEP scores (OR 2.35 95% CI 1.1-5.03, p = 0.027) predicted poor worse eye final acuity. 16 children had homonymous hemianopias at follow up, predicted by poor presenting binocular VEP score (OR 1.449 95%CI 1.052-1.995, p = 0.02). CONCLUSIONS: We found that both RNFL thickness on OCT and VEP were useful in predicting future visual acuity and vision and potentially in planning treatment. We had a high prevalence of homonymous hemianopia.

The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

Contribution of elevation and residential proximity to the coast in explaining geographic variations in hip fracture incidence. A Norwegian Epidemiologic Osteoporosis Studies (NOREPOS) study.

A higher risk of hip fracture was found in areas of Norway at higher elevation and farther from the coast. However, the previously seen county variations could not be explained by these geographical factors. INTRODUCTION: Norway is an elongated country extending north of the Arctic Circle with substantial coast-inland variation in topography and climate. Differences in hip fracture incidence between counties and a distinct seasonal variation have previously been shown. The aim of the current study was to explore these variations further by considering associations of height above sea level (elevation) and distance to the coast with hip fracture incidence. METHODS: All patients with hip fractures admitted to Norwegian hospitals in the period 2009-2018 were included. Individual residential elevation and distance to the coast was calculated in Geographic Information Systems and combined with individual-level population data on all Norwegians 50 years of age or older during the observation period, including hospital information on fractures. Age-standardized incidences rate and incidence rate ratios with 95% confidence intervals (IRR, 95% CI) according to elevation and coastal proximity were estimated. The associations were tested using Poisson models adjusting for sex, urban/rural location of residency, country of birth, and season of hip fracture occurrence. RESULTS: From 2009 to 2018, there were 85,776 first hip fractures. There was an increasing risk with higher residential elevation (above versus below mean) for women: IRR = 1.04, 95% CI: 1.02, 1.05), but not for men (IRR = 1.00, 95% CI: 0.97, 1.02). Incidence of hip fracture increased with distance from the coast. Women residing the farthest away from the coast (above versus below mean distance) had a higher age-adjusted incidence of hip fracture compared to those living closer to the coast (IRR = 1.04 (95% CI: 1.02, 1.06), whereas no association was found in men (IRR = 1.00 (95% CI: 1.00, 1.01). Combining elevation and distance to coast showed a higher incidence in women living at high elevation far from the coast compared with women living at low elevation near the coast (IRR = 1.07, 95% CI: 1.04, 1.10). A similar result was found in men but only for hip fractures occurring during March-May (IRR = 1.07, 95% CI: 1.00, 1.15). The previously shown patterns of county differences and seasonal variations were unchanged when considering geography. CONCLUSION: We found a somewhat higher incidence of hip fracture in inland residents living in areas of high elevation, as compared to those living in more coastal proximity; however, the geographic variation did not explain county and seasonal differences in fracture incidence in Norway. More in-depth analyses on temperature and climate factors may give further clues.

Geographic variations in hip fracture incidence in a high-risk country stretching into the Arctic: a NOREPOS study.

There are geographic variations in hip fracture incidence rates across Norway, with a lower incidence in the coastal areas of the southwest and in the Arctic north, contrary to what may be expected with regard to vitamin D exposure from sunlight. The regional differences have become smaller in recent years. INTRODUCTION: To investigate geographic variation in hip fracture incidence within Norway and regional differences in time trends. METHODS: All hip fractures treated in Norwegian hospitals 2002-2013 were included, and demographic information was obtained from Statistics Norway. Age-standardized incidence rates were calculated separately for 19 counties. Incidence rate ratios with 95% confidence intervals for county differences and time trends were estimated using Poisson regression. RESULTS: Age-standardized number of hip fractures per 10,000 person-years varied between counties from 69 to 84 in women and from 34 to 41 in men. The highest rates were observed in the southeastern capital city of Oslo, while rates were low in the four northernmost counties. There was an east-west gradient, with lower incidence in the coastal southwest compared with the southeast. Women showed a statistically significant decline during 2002-2013 in almost all counties (up to 31%). In men, only a few counties showed a decline. In both genders, hip fracture rates at age 80 in the combined five counties with the highest rates were significantly higher than in the combined five counties with the lowest rates across the period, although the trends converged over time. CONCLUSIONS: In Norway, the hip fracture incidence was lower in the north compared with the south. In addition, we observed an east-west gradient with the highest incidence in the southeast and lower incidence in the coastal southwest. While there has been an overall declining trend in hip fracture incidence over time, regional differences are still apparent.

Determinants of trabecular bone score and prevalent vertebral fractures in women with fragility fractures: a cross-sectional sub-study of NoFRACT.

Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1-SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1-SQ3 fractures. SQ1-SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS. INTRODUCTION: Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1-SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1-SQ3 fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1-SQ3 fracture assessed. RESULTS: Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1-SQ3 fractures. In multiple variable analysis, higher age (ßper SD = - 0.26, 95% CI: - 0.36,- 0.15), parental hip fracture (ß = - 0.29, 95% CI: - 0.54,- 0.05), and daily alcohol intake (ß = - 0.43, 95% CI - 0.79, - 0.08) were associated with lower TBS. Higher BMD of femoral neck (ßper SD = 0.34, 95% CI 0.25-0.43) and lumbar spine (ßper SD = 0.40, 95% CI 0.31-0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (ORper SD = 1.94, 95% CI 1.51-2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09-2.71) were positively associated with SQ1-SQ3 fractures, while lumbar spine BMD (ORper SD = 0.75 95% CI 0.60-0.95) was negatively associated with SQ1-SQ3 fractures. No association between TBS and SQ1-SQ3 fractures was found. CONCLUSION: Since TBS and SQ1-SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment.

Renal tumor biopsies are associated with a low complication rate.

BACKGROUND: Due to the high incidence of benign lesions in renal masses, numerous studies have been performed to clarify the value of core needle biopsies. The aim of the present study was to describe the complication rate after renal tumor biopsies (RTB), in order to make recommendations on observation after the procedure. MATERIALS AND METHODS: Data from all patients who underwent percutaneous ultrasound-guided RTB between February 2013 and October 2016 due to CT verified solid renal masses were prospectively collected and kept in a well-maintained database. Complications were collected retrospectively and classified according to the Clavien-Dindo (CD) classification system. RESULTS: Data from 224 consecutive patients were retrieved. Thirteen patients underwent unilateral repeat biopsies and three patients underwent bilateral biopsies; thus, a total of 240 procedures were analyzed. A total of 124 patients (51.7%) were discharged within 4 hours after the RTB procedures and 110 patients (45.8%) were discharged within 24 hours. The remaining six patients (2.5%) were hospitalized for more than 1 day, all due to co-morbidities which were unrelated to the procedure. In total, five patients (2.1%) experienced post-biopsy complications: one case of iatrogenic pneumothorax, one case of spontaneously resolving hematuria and three cases of fever. All complications were CD ≤2 and all patients with complications were discharged within 24 hours, except for one patient who was hospitalized for 3 days due to management of bone pain. No correlation was found between the number of biopsies and complication rate. CONCLUSION: The overall complication rate following ultrasound-guided biopsies of renal tumors was low and all complications were mild. Given the current evidence, it is believed that ultrasound-guided RTB can be done as an outpatient procedure without the need for hospitalization.

Core needle biopsy clarify the histology of the small renal masses and may prevent overtreatment.

PURPOSE: The purpose of the study was to evaluate the diagnostic accuracy of core biopsy in small renal masses ≤ 4 cm in response to the rising prevalence of renal masses. METHODS: Data from 129 consecutive patients who underwent biopsies of solid renal masses of ≤ 4 cm were prospectively collected between September 2014 and January 2017. In cases with inconclusive biopsies, a repeat biopsy was recommended. Histology from surgical specimens was used as gold standard to evaluate the accuracy of renal biopsies. RESULTS: The initial biopsies revealed malignancy in 77 patients (59.7%) and benign histology in 35 patients (27.1%), whereas 17 (13.2%) were inconclusive. Fifty-six patients with malignant histology underwent either partial or radical nephrectomy according to the physicians' recommendation, while two patients with benign histology requested surgery. In all cases, the biopsy diagnosis was confirmed upon final histopathology. Of the inconclusive cases, six underwent repeat biopsies all with benign histology. Further, three patients opted for immediate partial nephrectomy with benign oncocytoma in two and renal cell carcinoma in the third. The remaining eight patients opted for follow-up CT scans with no sign of progression with a minimum of 6-month follow-up. No biopsy related complications were reported in the first 30 days after RTB. Overall, the treatment strategy changed in 45 of 129 (35%) patients due to biopsy results. This was either due to benign findings or due to the discovery of non-renal cell cancers. CONCLUSION: Core needle biopsies of solid renal masses ≤ 4 cm have excellent accuracy and may be used to select the correct treatment. Importantly, they may serve to prevent overtreatment of benign tumors.

Dark Matter Search Results from the PICO-60 C_{3}F_{8} Bubble Chamber.

New results are reported from the operation of the PICO-60 dark matter detector, a bubble chamber filled with 52 kg of C_{3}F_{8} located in the SNOLAB underground laboratory. As in previous PICO bubble chambers, PICO-60 C_{3}F_{8} exhibits excellent electron recoil and alpha decay rejection, and the observed multiple-scattering neutron rate indicates a single-scatter neutron background of less than one event per month. A blind analysis of an efficiency-corrected 1167-kg day exposure at a 3.3-keV thermodynamic threshold reveals no single-scattering nuclear recoil candidates, consistent with the predicted background. These results set the most stringent direct-detection constraint to date on the weakly interacting massive particle (WIMP)-proton spin-dependent cross section at 3.4×10^{-41} cm^{2} for a 30-GeV c^{-2} WIMP, more than 1 order of magnitude improvement from previous PICO results.

First Demonstration of a Scintillating Xenon Bubble Chamber for Detecting Dark Matter and Coherent Elastic Neutrino-Nucleus Scattering.

A 30-g xenon bubble chamber, operated at Northwestern University in June and November 2016, has for the first time observed simultaneous bubble nucleation and scintillation by nuclear recoils in a superheated liquid. This chamber is instrumented with a CCD camera for near-IR bubble imaging, a solar-blind photomultiplier tube to detect 175-nm xenon scintillation light, and a piezoelectric acoustic transducer to detect the ultrasonic emission from a growing bubble. The time of nucleation determined from the acoustic signal is used to correlate specific scintillation pulses with bubble-nucleating events. We report on data from this chamber for thermodynamic "Seitz" thresholds from 4.2 to 15.0 keV. The observed single- and multiple-bubble rates when exposed to a ^{252}Cf neutron source indicate that, for an 8.3-keV thermodynamic threshold, the minimum nuclear recoil energy required to nucleate a bubble is 19±6 keV (1σ uncertainty). This is consistent with the observed scintillation spectrum for bubble-nucleating events. We see no evidence for bubble nucleation by gamma rays at any of the thresholds studied, setting a 90% C.L. upper limit of 6.3×10^{-7} bubbles per gamma interaction at a 4.2-keV thermodynamic threshold. This indicates stronger gamma discrimination than in CF_{3}I bubble chambers, supporting the hypothesis that scintillation production suppresses bubble nucleation by electron recoils, while nuclear recoils nucleate bubbles as usual. These measurements establish the noble-liquid bubble chamber as a promising new technology for the detection of weakly interacting massive particle dark matter and coherent elastic neutrino-nucleus scattering.

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.

Dark Matter Search Results from the PICO-2L C3F8 Bubble Chamber.

New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.

Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure.

OBJECTIVES: Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF. DESIGN: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored. RESULTS: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005). CONCLUSIONS: TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.

Abdominal obesity increases the risk of hip fracture. A population-based study of 43,000 women and men aged 60-79 years followed for 8 years. Cohort of Norway.

BACKGROUND: The question as to whether abdominal obesity has an adverse effect on hip fracture remains unanswered. The purpose of this study was to investigate the associations of waist circumference, hip circumference, waist-hip ratio, and body mass index with incident hip fracture. METHODS: The data in this prospective study is based on Cohort of Norway, a population-based cohort established during 1994-2003. Altogether 19,918 women and 23,061 men aged 60-79 years were followed for a median of 8.1 years. Height, weight, waist and hip circumference were measured at baseline using standard procedures. Information on covariates was collected by questionnaires. Hip fractures (n = 1,498 in women, n = 889 in men) were identified from electronic discharge registers from all general hospitals in Norway between 1994 and 2008. RESULTS: The risk of hip fracture decreased with increasing body mass index, plateauing in obese men. However, higher waist circumference and higher waist-hip ratio were associated with an increased risk of hip fracture after adjustment for body mass index and other potential confounders. Women in the highest tertile of waist circumference had an 86% (95% CI: 51-129%) higher risk of hip fracture compared to the lowest, with a corresponding increased risk in men of 100% (95% CI 53-161%). Lower body mass index combined with abdominal obesity increased the risk of hip fracture considerably, particularly in men. CONCLUSION: Abdominal obesity was associated with an increased risk of hip fracture when body mass index was taken into account. In view of the increasing prevalence of obesity and the number of older people suffering osteoporotic fractures in Western societies, our findings have important clinical and public health implications.

The "bacterial heterodisulfide" DsrC is a key protein in dissimilatory sulfur metabolism.

DsrC is a small protein present in organisms that dissimilate sulfur compounds, working as a physiological partner of the DsrAB sulfite reductase. DsrC contains two redox active cysteines in a flexible carboxy-terminal arm that are involved in the process of sulfite reduction or sulfur(1) compound oxidation in sulfur-reducing(2) or sulfur-oxidizing(3) organisms, respectively. In both processes, a disulfide formed between the two cysteines is believed to serve as the substrate of several proteins present in these organisms that are related to heterodisulfide reductases of methanogens. Here, we review the information on DsrC and its possible physiological partners, and discuss the idea that this protein may serve as a redox hub linking oxidation of several substrates to dissimilative sulfur metabolism. In addition, we analyze the distribution of proteins of the DsrC superfamily, including TusE that only requires the last Cys of the C-terminus for its role in the biosynthesis of 2-thiouridine, and a new protein that we name RspA (for regulatory sulfur-related protein) that is possibly involved in the regulation of gene expression and does not need the conserved Cys for its function. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart.

BACKGROUND AND PURPOSE: Levosimendan is known as a calcium sensitizer, although it is also known to inhibit PDE3. We aimed to isolate each component and estimate their contribution to the increased cardiac contractility induced by levosimendan. EXPERIMENTAL APPROACH: Contractile force was measured in electrically stimulated ventricular strips from explanted failing human hearts and left ventricular strips from normal male Wistar rats. PDE activity was measured in a two-step PDE activity assay on failing human ventricle. KEY RESULTS: Levosimendan exerted a positive inotropic effect (PIE) reaching maximum at 10(-5) M in ventricular strips from failing human hearts. In the presence of the selective PDE3 inhibitor cilostamide, the PIE of levosimendan was abolished. During treatment with a PDE4 inhibitor and a supra-threshold concentration of isoprenaline, levosimendan generated an amplified inotropic response. This effect was reversed by ß-adrenoceptor blockade and undetectable in strips pretreated with cilostamide. Levosimendan (10(-6) M) increased the potency of ß-adrenoceptor agonists by 0.5 log units in failing human myocardium, but not in the presence of cilostamide. Every inotropic response to levosimendan was associated with a lusitropic response. Levosimendan did not affect the concentration-response curve to calcium in rat ventricular strips, in contrast to the effects of a known calcium sensitizer, EMD57033 [5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one]. PDE activity assays confirmed that levosimendan inhibited PDE3 as effectively as cilostamide. CONCLUSIONS AND IMPLICATIONS: Our results indicate that the PDE3-inhibitory property of levosimendan was enough to account for its inotropic effect, leaving a minor, if any, effect to a calcium-sensitizing component.

The cardiokine secreted Frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure.

OBJECTIVES: Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled-related protein 3 (sFRP3), a modulator of Wnt signalling, is related to the progression of HF. DESIGN: Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI-HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch. RESULTS: (i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow-up of 47 months, 315 patients died in the GISSI-HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all-cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT-proBNP, the associations with mortality remained significant for the third tertile (all-cause, HR 1.45, P = 0.011; cardiovascular, HR 1.66, P = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post-MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts. CONCLUSION: There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.

Is the quality of drinking water a risk factor for self-reported forearm fractures? Cohort of Norway.

SUMMARY: Compared to pH ≥7.0 in Norwegian municipal drinking water, pH <7.0 increased the risk of forearm fractures in the population-based Cohort of Norway (CONOR; n = 127,272). The association was attenuated (p > 0.05) after adjustments for indicators of bacteria and organic matter, which may signify an association between poor drinking water and bone health. INTRODUCTION: The Norwegian population has the highest rate of fractures ever reported. A large variation in fracture rate both between and within countries indicates that an environmental factor, such as the quality of drinking water, could be one of the causes of the disparities. Our aim was to investigate a possible association between pH (an important parameter for water quality) and self-reported forearm fracture and to examine whether other water quality factors could account for this association. METHODS: Using Geographic Information Systems, information on the quality of drinking water was linked to CONOR (n = 127,272; mean age, 50.2 ± 15.8 years), a database comprising ten regional epidemiological health surveys from across the country in the time period 1994-2003. RESULTS: The highest risk of forearm fracture was found at a pH of around 6.75, with a decreasing risk toward both higher and lower pH values. The increased adjusted odds of forearm fracture in men consuming municipal drinking water with pH <7.0 compared to water with pH ≥7.0 was odds ratio (OR) = 1.19 (95 % CI, 1.14, 1.25), and the corresponding increased odds in women was OR = 1.14 (95 % CI, 1.08, 1.19). This association was attenuated (p > 0.05) after further adjustments for other water quality factors (color grade, intestinal enterococci, and Clostridium perfringens). CONCLUSIONS: Our findings indicate a higher risk of fracture when consuming water of an acidic pH; however, the risk does not only seem to be due to the acidity level per se, but also to other aspects of water quality associated with pH.