Miracle-dz/UniFAR-FTUs huggingface dataset:
Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy.

AIMS Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM. METHODS AND RESULTS The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T(3)) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T(3) levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T(3) from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction. CONCLUSION Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM.
Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11betaHSD1-deficient mice post-MI.

AIMS Mice unable to locally regenerate corticosterone due to deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) have enhanced angiogenesis during acute myocardial infarct healing. The present study investigates the hypotheses that in these mice (i) inflammation and angiogenic signalling are promoted and (ii) longer-term remodelling and function are improved. METHODS AND RESULTS Myocardial infarction (MI) was induced by coronary artery ligation in 11βHSD1(-/-) and wild-type (C57BL/6) mice. Studies were terminated 2, 4, 7, and 28 days post-surgery. Increased vessel density (CD31 immunoreactivity) on the infarct border was confirmed 7 days after MI in 11βHSD1(-/-) hearts (P < 0.05) and was accompanied by improved ejection fraction (ultrasound) compared with C57BL/6. During wound healing, recruitment of neutrophils (at 2 days after MI) and macrophages (from 4 days after MI) and expression of monocyte-chemoattractant protein-1 was increased in 11βHSD1(-/-) compared with C57BL/6 hearts (P < 0.05). Recruitment of alternatively activated YM1-positive macrophages was particularly enhanced in the period preceding increased vessel density and was accompanied by increased expression of pro-angiogenic IL-8. By 28 days post-MI, when the infarct scar had matured, higher vessel density was maintained in 11βHSD1(-/-) hearts and vessels were smooth-muscle coated. Infarct scars were thicker (P < 0.001) in 11βHSD1(-/-) compared with C57BL/6 hearts and ejection fraction was higher (P < 0.05). CONCLUSION Increased vessel density in healing infarcts of mice deficient in 11(-/-)HSD1 follows recruitment of pro-reparative macrophages and increased pro-angiogenic signalling. Mature infarcts show less thinning and cardiac function is improved relative to wild-type mice, suggesting that 11βHSD1 may be a novel therapeutic target after MI.
Acute selenium toxicity associated with a dietary supplement.

BACKGROUND Selenium is an element necessary for normal cellular function, but it can have toxic effects at high doses. We investigated an outbreak of acute selenium poisoning. METHODS A case was defined as the onset of symptoms of selenium toxicity in a person within 2 weeks after ingesting a dietary supplement manufactured by "Company A," purchased after January 1, 2008. We conducted case finding, administered initial and 90-day follow-up questionnaires to affected persons, and obtained laboratory data where available. RESULTS The source of the outbreak was identified as a liquid dietary supplement that contained 200 times the labeled concentration of selenium. Of 201 cases identified in 10 states, 1 person was hospitalized. The median estimated dose of selenium consumed was 41 749 microg/d (recommended dietary allowance is 55 microg/d). Frequently reported symptoms included diarrhea (78%), fatigue (75%), hair loss (72%), joint pain (70%), nail discoloration or brittleness (61%), and nausea (58%). Symptoms persisting 90 days or longer included fingernail discoloration and loss (52%), fatigue (35%), and hair loss (29%). The mean initial serum selenium concentration of 8 patients was 751 microg/L (reference range, < or =125 microg/L). The mean initial urine selenium concentration of 7 patients was 166 microg/24 h (reference range, < or =55 microg/24 h). CONCLUSIONS Toxic concentrations of selenium in a liquid dietary supplement resulted in a widespread outbreak. Had the manufacturers been held to standards used in the pharmaceutical industry, it may have been prevented.
A population-based study of inferior vena cava filters in patients with acute venous thromboembolism.

BACKGROUND Our study objective was to describe the frequency, indications, and outcomes after inferior vena cava (IVC) filter placement in a population-based sample of residents of the Worcester, Massachusetts, metropolitan area who had been diagnosed as having acute venous thromboembolism (VTE) in 1999, 2001, and 2003. METHODS A retrospective chart review of inpatient and outpatient medical records was conducted. Recorded indication(s) for IVC filter placement was determined among a subset of cases from 3 Worcester tertiary care hospitals. Three thrombosis specialists assessed the appropriateness of IVC filter placement. RESULTS Of 1547 greater Worcester residents with validated acute VTE and without a prior IVC filter, 203 (13.1%) had an IVC filter placed after acute VTE. Patients with an IVC filter were older, had more comorbidities, and had a higher mortality rate during 3 years of follow-up. There was unanimous agreement by panel members that the use of an IVC filter was appropriate in 51% of cases and inappropriate in 26% of cases, with no consensus in the remaining 23%. CONCLUSIONS In this community-based study, IVC filters were frequently used in the treatment of patients with acute VTE. Placement was deemed to be appropriate in approximately 50% of the patients but was not appropriate or debatable in the remaining cases. Given the increasing use of IVC filters, prospective studies are clearly needed to better define the indications for, and efficacy of, IVC filter placement.
Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury.

AIMS Endothelial regeneration after vascular injury, including percutaneous coronary intervention, is essential for vascular homeostasis and inhibition of neointima formation. Circulating endothelial progenitor cells (EPCs) have been implicated to contribute by homing and differentiating into endothelial cells (ECs). We tested this theory in a murine arterial injury model using carotid artery transplants and fluorescent reporter mice. METHODS AND RESULTS Wire-injured carotid artery segments from wild-type mice were transplanted into TIE2-GFP transgenic mice expressing green fluorescent protein (GFP) in ECs. We found that the endothelium regenerated with GFP(+) ECs as a function of time, evolving from the anastomosis sites towards the centre of the transplant. A migration front of ECs at Day 7 was verified by scanning electron microscopy and by bright-field microscopy using recipient TIE2-lacZ mice with endothelial β-galactosidase expression. These experiments indicated migration of flanking ECs rather than homing of circulating cells as the underlying mechanism. To confirm this, we interposed non-injured wild-type carotid artery segments between the denuded transplant and the TIE2-GFP recipient mouse. Among 1186 ECs identified in re-endothelialized transplants (n= 5) by staining for von Willebrand Factor or vascular endothelial-cadherin, we did not find any blood-derived (GFP(+)) cells. CONCLUSION Endothelial regeneration after vascular injury did not involve circulating EPCs but was mediated solely by migration of ECs from the adjacent healthy endothelium.
Lack of follow-up after fecal occult blood testing in older adults: inappropriate screening or failure to follow up?

BACKGROUND It is unclear whether lack of follow-up after screening fecal occult blood testing (FOBT) in older adults is due to screening patients whose comorbidity or preferences do not permit follow-up vs failure to complete follow-up in healthy patients. METHODS A prospective cohort study of 2410 patients 70 years or older screened with FOBT was conducted at 4 Veteran Affairs (VA) medical centers from January 1 to December 31, 2001. The main outcome measure was receipt of follow-up within 1 year of FOBT based on national VA and Medicare data. For patients with positive FOBT results, age and Charlson comorbidity scores were evaluated as potential predictors of receiving a complete colon evaluation (colonoscopy or sigmoidoscopy plus barium enema), and medical records were reviewed to determine reasons for lack of follow-up. RESULTS A total of 212 patients (9%) had positive FOBT results; 42% received a complete colon evaluation within 1 year. Age and comorbidity were not associated with receipt of a complete follow-up, which was similar among patients 70 to 74 years old with a Charlson score of 0 compared with patients 80 years or older with a Charlson score of 1 or higher (48% vs 41%; P=.28). The VA site, number of positive FOBT cards, and number of VA outpatient visits were predictors. Of 122 patients who did not receive a complete follow-up within 1 year, 38% had documentation that comorbidity or preferences did not permit follow-up, and over the next 5 years 76% never received a complete follow-up. CONCLUSIONS While follow-up after positive FOBT results was low regardless of age or comorbidity, screening patients in whom complete evaluation would not be pursued substantially contributes to lack of follow-up. Efforts to improve follow-up should address the full chain of decision making, including decisions to screen and decisions to follow up.
Early-diastolic left ventricular lengthening implies pulmonary hypertension-induced right ventricular decompensation.

AIMS In chronic pulmonary hypertension (PH), right ventricular (RV) failure is associated with shortening of the RV free wall (RVFW) beyond pulmonary valve closure, temporarily paralleled by pronounced lengthening of the left ventricular free wall (LVFW). We hypothesized that this early-diastolic LVFW lengthening is caused by altered RVFW myofibre function and may therefore serve as a non-invasive measure of PH-induced RV (dys)function. METHODS AND RESULTS In 22 idiopathic pulmonary arterial hypertension (IPAH) patients, five chronic thrombo-embolic PH (CTEPH) patients, and six healthy subjects, ventricular volumes and circumferential strains were obtained using magnetic resonance imaging. RV ejection fraction (RVEF) and stroke volume index (RVSVI) were smaller in IPAH and CTEPH patients than in normals (RVEF: 32 ± 12 and 23 ± 19 vs. 59 ± 14%, respectively, both P < 0.01; RVSVI: 32 ± 9 and 23 ± 9 vs. 47 ± 6 mL/m(2), both P < 0.001). LV early-diastolic strain index (LVEDSI), defined as LVFW strain in the period between LVFW and RVFW peak shortening normalized for total systolic LVFW shortening, was larger in IPAH and CTEPH patients (0.52 ± 0.33 and 0.55 ± 0.40, both P < 0.01) than in normals (-0.03 ± 0.03). LVEDSI correlated negatively with RVEF (R = -0.74, P < 0.0001) and RVSVI (R = -0.69, P < 0.0001). Three multi-scale computer simulations of PH (all with mean pulmonary artery pressure = 55 mmHg) with complete, incomplete, and no structural adaptation of ventricular walls to local myofibre load showed that LVEDSI increased with deficiency of cardiac adaptation to PH (0.01, 0.52, and 0.84, respectively). CONCLUSION Early-diastolic LV lengthening reflects inadequate structural adaptation of the RVFW to increased myofibre load and is therefore a useful, non-invasive, and easily obtainable predictor of PH-induced RV dysfunction.
Sophisticated Mediators: New Zealand-Born Samoan First-Time Mothers and Strategies for Their Health and Wellbeing

This thesis explores the experiences of four New Zealand-born Samoan first time mothers during pregnancy, childbirth and early motherhood living in Wellington. The impetus for this research arose from findings that showed a considerable variation in the prevalence of postnatal depression between Samoan women (7.6%), Tongan women (30.9%) and others (20% for all New Zealand mothers). Qualitative, face-to-face individual interviews were conducted within a qualitative feminist framework. The two interviews with each woman were conducted during the last trimester of their pregnancy (28+weeks gestation); and 12 months post-birth. The thesis drew upon the four-element model – Epistemology, Theoretical Perspective, Methodology and Methods to provide a framework to conceptualise and clarify the foundation for this research project. Thus the thesis is best described as a feminist phenomenological social constructionist approach. The findings revealed the women of this study were „Sophisticated Mediators‟ who, although faced with many challenges throughout their pregnancy, childbirth and early motherhood experiences, mediated successfully between, and within, existing cultural and belief systems i.e. Samoan traditional values and New Zealand cultural system; to acquire or maintain resilience toward depressive symptoms during early motherhood. Support structures such as family, in particular mothers, proved to be a vital source of support for the women. Recommendations arising from the research are targeted at support providers and family members and this is discussed in detail. Antenatal care was important although antenatal classes not so; conversely, the women were high adopters of technology in the form of the internet to access information. It is vital for support providers to recognise the high regard the women had for the internet as a source of valuable and easily accessible information, and utilise those avenues more to provide information that will complement or improve the existing support structures. During the antenatal period, women should be encouraged to develop or strengthen relationships with a significant female who will be with them throughout the childbirth and early motherhood process.
Activation of the alternative pathway of complement during the acute phase of typical haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is characterized by haemolytic anaemia, thrombocytopenia and acute renal failure. We studied the activation state of classical and alternative pathways of complement during the acute phase of Shiga toxin‐associated HUS by performing a prospective study of 18 patients and 17 age‐matched healthy controls to evaluate C3, C3c, C4, C4d, Bb and SC5b‐9 levels. SC5b‐9 levels were increased significantly in all patients at admission compared to healthy and end‐stage renal disease controls, but were significantly higher in patients presenting with oliguria compared to those with preserved diuresis. C3 and C4 levels were elevated significantly at admission in the non‐oliguric group when compared to controls. No significant differences were found for C4d values, whereas factor Bb was elevated in all patients and significantly higher in oliguric patients when compared to both controls and non‐oliguric individuals. A positive and significant association was detected when Bb formation was plotted as a function of plasma SC5b‐9 at admission. Bb levels declined rapidly during the first week, with values not significantly different from controls by days 3 and 5 for non‐oligurics and oligurics, respectively. Our data demonstrate the activation of the alternative pathway of complement during the acute phase of Stx‐associated HUS. This finding suggests that complement activation may represent an important trigger for the cell damage that occurs during the syndrome.
M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis.

AIMS The goal of this study was to characterize the role of inflammatory macrophages in the induction of the vascular smooth muscle cell (VSMC)-mediated formation of aortic tertiary lymphoid organs (TLOs). METHODS AND RESULTS Mouse bone marrow-derived M1 macrophages acted as lymphoid tissue inducer cells. Indeed, they expressed high levels of tumour necrosis factor (TNF)-α and membrane-bound lymphotoxin (LT)-α, two inducing cytokines that triggered expression of the chemokines CCL19, CCL20, and CXCL16, as did M1 supernatant. The blockade of LTβR signalling with LTβR-Ig had no effect, whereas that of TNFR1/2 signalling reduced chemokine expression by VSMCs in both wild-type (WT) and LTβR KO mice, demonstrating that LTβR signalling is dispensable for the M1-inducing effect. This effect was corroborated by the development of TLOs observed in LTβR KO->apolipoprotein E knockout (ApoE KO) aortic segments after orthotopic transplantation. Furthermore, treatment of ApoE KO mice with anti-TNF-α antibody decreased the number and incidence of aortic TLOs. Finally, lymphoid nodules composed of T and B cells formed in in vivo-implanted scaffolds seeded with VSMCs previously stimulated ex vivo by M1-conditioned medium. CONCLUSIONS These results are the first to identify M1 macrophages as inducer cells that trigger the expression of chemokines by VSMCs independently of LTβR signalling. We propose that the dialogue between macrophages and VSMCs-established across the vascular wall-contributes to the formation of aortic TLOs.
Defective autophagosome trafficking contributes to impaired autophagic flux in coronary arterial myocytes lacking CD38 gene.

AIM Autophagic flux is an important process during autophagy maturation in smooth muscle cells. However, the molecular mechanisms underlying autophagic flux in these cells are largely unknown. Here, we revealed a previously undefined role of CD38, an enzyme that metabolizes NADP(+) into NAADP, in the regulation of autophagic flux in coronary arterial myocytes (CAMs). METHODS AND RESULTS In vivo CD38 gene knockout mice (CD38(-/-)) fed the high-fat Western diet showed increased accumulation of autophagosomes in coronary arterial media compared with that in wild-type (CD38(+/+)) mice, suggesting that CD38 gene deletion results in a defective autophagic process in CAMs of coronary arteries. In primary cultured CAMs, CD38 gene deletion markedly enhanced 7-ketocholesterol (7-Ket, an atherogenic stimulus and autophagy inducer)-induced accumulation of autophagosomes and increased expression of an autophagic marker, LC3B. However, no difference in autophagosome formation was observed between CD38(+/+) and CD38(-/-) CAMs when autophagic flux was blocked, which indicates that CD38 regulates autophagic flux rather than induction of autophagosome formation. Further, 7-Ket-induced formation of autophagolysosomes was markedly attenuated in CD38(-/-) CAMs compared with CD38(+/+) CAMs. Mechanistically, CD38 gene deletion markedly inhibited 7-Ket-induced dynein activation and autophagosome trafficking, which were associated with attenuated lysosomal Ca(2+) release. Importantly, coronary arterial smooth muscle from CD38(-/-) mice fed the Western diet exhibited phenotypic changes towards a more dedifferentiated state with abnormal extracellular matrix metabolism. CONCLUSION Taken together, these results suggest that CD38 plays a critical role in autophagosome trafficking and fusion with lysosomes, thus controlling autophagic flux in CAMs under atherogenic stimulation.
E cient Monte Carlo Pricing of Basket Options

Montecarlo methods can be used to price derivatives for which closed evaluation formulas are not available or di cult to derive. A drawback of the method can be its high computational cost, especially if applied to basket options, whose payo s depend on more than one asset. This article presents two kinds of control variates to reduce variance of estimates, based on unconditional and conditional expectations of assets respectively. We apply the previous variance reduction methods to some basket options (Spread, Dual and Portfolio options), achieving in some case remarkable speed and accuracy in price estimation.
SRT1720 counteracts glucosamine-induced endoplasmic reticulum stress and endothelial dysfunction.

AIMS We hypothesized that a disproportionate activation of the glucosamine (GlcN) pathway, caused by a prolonged exposure to hyperglycaemia, could impair endothelial integrity promoting endoplasmic reticulum (ER) stress. We also tested the possibility that SRT1720 may be able to counteract GlcN-induced ER stress. METHODS AND RESULTS Human umbilical vein endothelial cells (HUVECs), human cardiac microvascular endothelial cells, and human retinal endothelial cells were treated with GlcN in the presence or absence of the chemical chaperone phenyl butyric acid (PBA) or SRT1720. Expression of ER stress markers, activation of apoptosis, and pro-inflammatory/pro-thrombotic pathways were evaluated by western blot, real-time RT-PCR, and ELISA assays. GlcN treatment resulted in a significantly increased expression of the major ER stress mediators. ER stress activation was paralleled by increased levels of apoptotic markers and by pro-inflammatory/pro-coagulant pathway activation. In HUVECs, ER stress inhibition by PBA alleviated a GlcN-induced pro-apoptotic and pro-inflammatory/pro-thrombotic state, suggesting a crucial role of ER stress in endothelial dysfunction caused by GlcN. Furthermore, SRT1720 treatment abolished GlcN-induced ER stress and reversed its effects on apoptosis and pro-inflammatory/pro-coagulant pathways. This SRT1720 action was mediated by its ability to modulate Raptor acetylation, thus inhibiting mammalian target of Rapamycin complex 1 (mTORC1)-dependent protein synthesis and alleviating ER overload. CONCLUSIONS Our data show that GlcN promotes a pro-apoptotic and pro-inflammatory/pro-thrombotic phenotype in endothelial cells by activating ER stress. The observation that SRT1720, inhibiting ER stress, was able to counteract GlcN effects lays the basis for future studies aimed to exploit this drug and cognate compounds in the treatment of endothelial dysfunction and atherosclerosis.