It has been known that anthracycline-based chemotherapy has the potential to cause cardiac dysfunction in breast cancer patients; however, recently evidence has shown that the addition of trastuzumab increases this risk. The study objective was to compare the cost-effectiveness of monitoring for cardiotoxicity with B-type natriuretic peptide (BNP), multi-gated acquisition scanning (MUGA), echocardiography (ECHO) or no monitoring from a payer’s prospective. Cost-effectiveness was compared between alternatives using an incremental cost-effectiveness ratio with outcomes of 1) quality-adjusted life-years and 2) percentage of patients diagnosed with each monitoring strategy. Costs estimates (in 2010 U.S. Dollars) of each strategy (obtained from the Center for Medicare and Medicaid Services website [www.cms.gov]) included the cost of the test, cost of treating heart failure once discovered (which includes medications, routine office visits, medication management) and the cost of potential acute care (which includes emergency department visits and hospitalizations). Estimates for the probabilities of heart failure development, disease progression, need for acute care, and mortality, as well as utility estimates for all disease stages were obtained from published literature. A 15-year time-frame was used with a 3% discount rate for both costs and QALYs. In the base-case analysis, the average costs and QALYs for monitoring patients were $10,062/ 6.92 QALY, $13,627/4.22 QALY, $14,739/ 6.61 QALY and $15,656/ 6.49 QALY for BNP, No Monitoring, ECHO and MUGA respectively. When comparing all alternatives to BNP, the ICER values were negative, indicating that BNP was the dominant monitoring strategy. Percent detection was similar between the three monitoring methods [21-22 % for HER-2(-) and 30-31% for HER-2(+) patients]. Again BNP was dominant over the other monitoring strategies. Sensitivity analyses were robust to changes in discount rate, probability of patients testing HER-2 (+), probability of patients being diagnosed in an asymptomatic stage, incidence of cardiac dysfunction in patients receiving anthracycline therapy ± trastuzumab and estimate of disutility associated with additional testing. A probabilistic sensitivity analysis conducted via Monte Carlo simulation led to the same conclusion as the base-case analysis; BNP was the dominant strategy over all monitoring alternatives. / text

Background and aims: Heart failure (HF) is a life threatening condition and optimal handling is necessary to reduce risk of therapy failure. The aims of this thesis were: (Paper I) to examine whether BNP (B-type natriuretic peptide)-guided HF treatment improves morbidity and mortality when compared with HF therapy implemented by a treating physician at sites experienced in managing patients with HF according to guidelines; (Paper II) to investigate how to define a responder regarding optimal cut-off level of BNP to predict death, need for hospitalisation, and worsening HF and to determine the optimal time to apply the chosen cut-off value; (Paper III) to evaluate how Health-Related Quality of Life (HR-QoL) is influenced by natriuretic peptide guiding and to study how HR-QoL is affected in responders compared to non-responders; (Paper IV) to evaluate the impact of patient age on clinical outcomes, and to evaluate the impact of duration of the HF disease on outcomes and the impact of age and HF duration on BNP concentration. Methods: A randomized, parallel group, multi-centre study was undertaken on 279 patients with HF and who had experienced an episode of worsening HF with increased BNP concentration. The control group (n=132) was treated according to HF guidelines and in the BNP-guided group (n=147) the HF treatment algorithm goal was to reduce BNP concentration to < 150 ng/L in patients < 75 years and <300 ng/L in patients > 75 years (Paper I), and to define the optimal percentage decrease in BNP and at what point during the follow-up to apply the definition (Paper II). To compare the BNP-guided group with the conventional HF treated group (Paper I), and responders and non-responders (Paper II) regarding HR-QoL measured with Short Form 36 (SF-36) at study start and at study end (Paper III) and to evaluate if age or HF duration influenced the HF outcomes and the influence of BNP on age and HF duration (Paper IV). Results: The primary outcome (mortality, hospitalisation and worsening HF) was not improved by BNP-guided HF treatment compared to conventional HF treatment or in any of the secondary outcome variables (Paper I). Applying a BNP decrease of at least 40 percent in week 16 (compared to study start) and/or a BNP<300 ng/L demonstrated the best risk reduction for cardiovascular mortality, by 78 percent and 89 percent respectively for HF mortality (Paper II). The HR-QoL improved in four domains in the BNP-guided group and in the control group in six of eight domains; however there were no significant differences between the groups (Paper III). For responders the within group analysis showed improvement in four domains compared to the non-responders that improved in one domain; however there were no significant differences between the two groups. There were improvements in HR-QoL in all four groups (Paper III). Age did not influence outcome but HF duration did. HF duration was divided into three groups: HF duration less than 1 year (group 1), 1-5 years (group 2) and >5 years (group 3). A 1.65-fold increased risk could be demonstrated in those with HF duration of more than five years compared to patients with short HF duration. The BNP concentration was increased with increased age, and there was a better response regarding BNP decrease in NP-guiding in patients with short HF duration, independent of age (Paper IV). Conclusions: There were no significant differences between BNP-guided HF treatment group and the group with conventional HF treatment as regards mortality, hospitalisation or HR-QoL. The responders to HF treatment showed a significantly better outcome in mortality and hospitalisation compared to non-responders but no significant differences in HR-QoL. The duration of HF might be an important factor to consider in HF treatment by BNP-guiding in the future.

No leite tipo \"B\" comercializado em São Paulo foram pesquisados a presença de aflatoxina M1 e de inibidores bacterianos (penicilina, água oxigenada, formol e cloro}. As amostras de leite utilizadas foram provenientes das quatro marcas de maior consumo pela população de São Paulo. O trabalho constituiu-se em um estudo longitudinal, com amostragem probabilística, dividido em dois períodos iguais de 140 dias com 224 amostras analisadas. No primeiro período, de 14 de junho a 31 de outubro de 1982, foram pesquisados todos os contaminantes propostos. No segundo período, de 01 de novembro de 1982 a 30 de março de 1983, a aflatoxina não foi pesquisada, pois, como sofre influência sazonal, há maior possibilidade de ser encontrada nos meses de temperaturas mais baixas. A aflatoxina, embora em baixos níveis e em pequena proporção (1 ,8 por cento ), fez-se presente nas quatro marcas. Foi constatada alta prevalência de inibidores bacterianos. No primeiro e no segundo período a proporção foi de 4,95 por cento e 4,50 por cento respectivamente. No primeiro período a incidência de resíduos de penicilina e de inibidores não identificados foi de 0,9 por cento , e de 3,6 por cento respectivamente. No segundo foi de 0,45 por cento e de 3,15 por cento . Houve uma baixa proporção de amostras com água oxigenada e formal, e ausência de cloro. De acordo com os resultados, concluiu-se que há necessidade do estabelecimento de limites de tolerância para a aflatoxina no leite, ausentes na nossa legislação; e pela necessidade da atuação da Saúde Pública através de inspeção, e através de amplos programas educativos junto aos produtores e indústrias. / B-type milk sold in the city of São Paulo, Brazil, was examined for Aflatoxin M1 and bacterial inhibitors, such as penicilin, hydrogen peroxide, formaldehyde and chlorine. Samples were taken from the faur most consumed brands. The study was longitudinal, with probabilistic sampling, divided in two equals periods of 140 days each; the total number studied was 224 in each period. During the first period, June 14 th through October, 31st, 1982, all mentioned contaminants were studied where as aflatoxin was not studied in the second period, November 1st, 1982 through March, 30th, 1983, as its occurrence is seasonal and the probability of it being encountered is practically null. Aflatoxin, although is small proportion (1.8%) and at low levels, was present in the four brands studied. The prevalence of bacterial inhibitors was high is both periods (4.95% in the first period and 4.50% in the second). During the first period the incidence of penicillin residues and non-identified inhibitors was 0.9% and 3.6% respectively, in the first period, and 0.45% and 3.15% respectively in the second. The proportion of samples containing hidrogen peroxide, formaldehyde was low and chlorine was absent in all. Our results show the need for establishing legal tolerance limits for aflatoxin in milk (which has not been done as yet) and the need for Public Health measures regarding inspection and education of productors and industrial plants.

Cardiovascular disease remains a leading a cause of mortality and morbidity. Primary prevention is known to reduce the incidence of cardiovascular disease. The use of medication is currently targeted at those at increased predicted risk of cardiovascular disease using risk prediction tools developed from large epidemiological studies. However these have poor external validity particularly for those at low or intermediate risk: a significant number of cardiovascular events still occurs in these groups. We hypothesised that screening for asymptomatic pre-clinical cardiovascular disease using B-type natriuretic peptide (BNP) and whole body contrast enhanced magnetic resonance imaging (MRI) could identify those at low/intermediate risk or disease whowill develop clinical disease and thus facilitate improved targeting of primary prevention at those most likely to benefit. The Tayside Screening for Cardiac Events (TASCFORCE) study is a prospective normal volunteer cohort study. Men and women aged 40 years or older free from cardiovascular disease and with a predicted 10-year coronary heart disease risk less than 20% were recruited. All had comprehensive baseline cardiovascular risk information and a BNP level measured. If the BNP level was greater than the median for their gender participants were invited to attend for a whole body contrast enhancedMRI scan comprising cardiac imaging and whole body angiography. The images were analysed to measure left ventricular mass (LVM), left ventricular volumes and left ventricular function. These were indexed for body size using height, height1.7, height2.7 and body surface area. Angiogram images were analysed for the presence and degree of intraluminal stenosis. All participants are being followed up using anonymised electronic data linkage for incident cardiovascular disease and death. 4423 participants (39.3% male) were recruited between November 2007 and February 2013. Median age was 51.2 years. The median 10-year coronary heart disease (CHD) 23 risk was 2% and 13.6% had a CHD risk of 10-19.9% (intermediate risk). The medianBNP results for men and women were 7.5 and 15.3 pg/ml respectively. Age, female sex and high density lipoprotein were independently associated with BNP level. Heart rate, total cholesterol and ex-smoking status were independently inversely associated with BNP level. 1528 (74.8% of those invited) underwent an MRI scan. Mean left ventricular mass was 129.2g and 87.0g for men and women respectively. LVM and left ventricular mass index (LVMI) were significantly higher in men than women. The vast majority (94.6%) of arterial segments analysed were normal and 50.6% of individuals had no evidence of luminal stenosis. From follow up data obtained 2 years after the end of recruitment 18,364 person years at risk were analysed. 17 cardiovascularevents and no deaths occurred in those not invited for an MRI scan based on their BNP result and 16 events and 1 death occurred in those invited for an MRI scan. There was no significant difference in event rates between those with above and below median BNP levels, between those with higher or lower LVM or LVMI or between those with and without the presence of stenosis on angiography. As expected we have not demonstrated the ability of LVM, LVMI or stenosis burden determined using magnetic resonance imaging to predict cardiovascular disease in a population at low or intermediate risk of CHD. We have also not demonstrated the ability of BNP to identify those at low orintermediate risk of CHD who will develop clinical CV disease. However it is the pre-planned longer-term follow up where difference might be expected. The low number of events at this early stage in follow up mean that it is difficult to draw firm conclusions. As follow up continues and further events accumulate we hope to determine if these measures will be shown to predict cardiovascular events in future analyses. We have characterised the normal values and distribution of a range of left ventricular structural and functional parameters derived using a steady state free precision sequence MRI in a population at low or intermediate risk of CHD which will provide a useful reference for normal values that are different to other imaging modalities including chocardiography and other protocols of MRI scanning.

In recent years, studies have revealed a central role for the intestine in regulation of lipid homeostasis and development of insulin resistance and type-2 diabetes. The function of intestinal Scavenger Receptor Class-B type-I remains unknown, however it is believed to play a role in dietary lipid uptake. Recently, our laboratory demonstrated a correlation between intestinal SR-BI expression and chylomicron secretion. We hypothesized that intestinal SR-BI is involved in chylomicron secretion and contributes to chylomicron oversecretion in insulin resistance. I first characterized chylomicron production in healthy and insulin resistant Syrian golden hamsters. Inhibition of SR-BI resulted in reduced postprandial chylomicron accumulation in plasma, and resistance to diet-induced hyperlipidemia and weight-gain. Lower postprandial triglyceride levels were also observed in SR-BI-/- mice. In summary, these data demonstrate a key role for intestinal SR-BI in chylomicron secretion and control of lipid homeostasis, implicating intestinal SR-BI in chylomicron overproduction in insulin resistant states.

In recent years, studies have revealed a central role for the intestine in regulation of lipid homeostasis and development of insulin resistance and type-2 diabetes. The function of intestinal Scavenger Receptor Class-B type-I remains unknown, however it is believed to play a role in dietary lipid uptake. Recently, our laboratory demonstrated a correlation between intestinal SR-BI expression and chylomicron secretion. We hypothesized that intestinal SR-BI is involved in chylomicron secretion and contributes to chylomicron oversecretion in insulin resistance. I first characterized chylomicron production in healthy and insulin resistant Syrian golden hamsters. Inhibition of SR-BI resulted in reduced postprandial chylomicron accumulation in plasma, and resistance to diet-induced hyperlipidemia and weight-gain. Lower postprandial triglyceride levels were also observed in SR-BI-/- mice. In summary, these data demonstrate a key role for intestinal SR-BI in chylomicron secretion and control of lipid homeostasis, implicating intestinal SR-BI in chylomicron overproduction in insulin resistant states.

No leite tipo \"B\" comercializado em São Paulo foram pesquisados a presença de aflatoxina M1 e de inibidores bacterianos (penicilina, água oxigenada, formol e cloro}. As amostras de leite utilizadas foram provenientes das quatro marcas de maior consumo pela população de São Paulo. O trabalho constituiu-se em um estudo longitudinal, com amostragem probabilística, dividido em dois períodos iguais de 140 dias com 224 amostras analisadas. No primeiro período, de 14 de junho a 31 de outubro de 1982, foram pesquisados todos os contaminantes propostos. No segundo período, de 01 de novembro de 1982 a 30 de março de 1983, a aflatoxina não foi pesquisada, pois, como sofre influência sazonal, há maior possibilidade de ser encontrada nos meses de temperaturas mais baixas. A aflatoxina, embora em baixos níveis e em pequena proporção (1 ,8 por cento ), fez-se presente nas quatro marcas. Foi constatada alta prevalência de inibidores bacterianos. No primeiro e no segundo período a proporção foi de 4,95 por cento e 4,50 por cento respectivamente. No primeiro período a incidência de resíduos de penicilina e de inibidores não identificados foi de 0,9 por cento , e de 3,6 por cento respectivamente. No segundo foi de 0,45 por cento e de 3,15 por cento . Houve uma baixa proporção de amostras com água oxigenada e formal, e ausência de cloro. De acordo com os resultados, concluiu-se que há necessidade do estabelecimento de limites de tolerância para a aflatoxina no leite, ausentes na nossa legislação; e pela necessidade da atuação da Saúde Pública através de inspeção, e através de amplos programas educativos junto aos produtores e indústrias. / B-type milk sold in the city of São Paulo, Brazil, was examined for Aflatoxin M1 and bacterial inhibitors, such as penicilin, hydrogen peroxide, formaldehyde and chlorine. Samples were taken from the faur most consumed brands. The study was longitudinal, with probabilistic sampling, divided in two equals periods of 140 days each; the total number studied was 224 in each period. During the first period, June 14 th through October, 31st, 1982, all mentioned contaminants were studied where as aflatoxin was not studied in the second period, November 1st, 1982 through March, 30th, 1983, as its occurrence is seasonal and the probability of it being encountered is practically null. Aflatoxin, although is small proportion (1.8%) and at low levels, was present in the four brands studied. The prevalence of bacterial inhibitors was high is both periods (4.95% in the first period and 4.50% in the second). During the first period the incidence of penicillin residues and non-identified inhibitors was 0.9% and 3.6% respectively, in the first period, and 0.45% and 3.15% respectively in the second. The proportion of samples containing hidrogen peroxide, formaldehyde was low and chlorine was absent in all. Our results show the need for establishing legal tolerance limits for aflatoxin in milk (which has not been done as yet) and the need for Public Health measures regarding inspection and education of productors and industrial plants.

In 1939, I.M. Sheffer proved that every polynomial sequence belongs to one and only one type. Sheffer extensively developed properties of the B-Type 0 polynomial sequences and determined which sets are also orthogonal. He subsequently generalized his classification method to the case of arbitrary B-Type k by constructing the generalized generating function A(t)exp[xH1(t) + · · · + xk+1Hk(t)] = ∑∞n=0 Pn(x)tn, with Hi(t) = hi,iti + hi,i+1t i+1 + · · · , h1,1 ≠ 0. Although extensive research has been done on characterizing polynomial sequences, no analysis has yet been completed on sets of type one or higher (k ≥ 1). We present a preliminary analysis of a special case of the B-Type 1 (k = 1) class, which is an extension of the B-Type 0 class, in order to determine which sets, if any, are also orthogonal sets. Lastly, we consider an extension of this research and comment on future considerations. In this work the utilization of computer algebra packages is indispensable, as computational difficulties arise in the B-Type 1 class that are unlike those in the B-Type 0 class.

Sepsis claims over 215,000 lives in the US annually. Inducible glucocorticoids (iGC) is produced during sepsis. However, the precise effects of iGC in sepsis remain unclear due to a lack of appropriate animal models. Glucocorticoid (GC) insufficiency is associated with a marked increase in mortality and occurs in 60% of severe septic patients. Yet the conclusion of GC therapy on septic patients is still controversial. Scavenger receptor class B type I (SR-BI) in the adrenal mediates the selective uptake of cholesteryl ester from lipoproteins for GC synthesis. SR-BI-/- mice completely lack iGC during sepsis and are highly susceptible to septic death, which presents SR-BI-/- mice as a GC insufficient model. However, SR-BI-/- mice display multiple defects contributing to septic death, making it difficult to study iGC by using these mice. Therefore, we utilized adrenal-specific SR-BI-/- mice (ADR-T SR-BI-/-) generated by adrenal transplantation. As expected, the ADR-T SR-BI-/- mice failed to generate iGC under cecal ligation and puncture (CLP)-induced sepsis and showed a significantly higher mortality than the control mice, demonstrating that iGC is essential for preventing septic death. High blood urea nitrogen (BUN) was observed in the ADR-T SR-BI-/- mice but not in the control mice in CLP, indicating that iGC protects kidney injury in sepsis. Plasma IL-6 was remarkably higher in the ADR-T SR-BI-/- mice than the control mice, demonstrating an anti-inflammatory effect of iGC in sepsis. The ADR-T SR-BI-/- mice also displayed significantly lower phagocytic activity of monocytes and neutrophils in the blood and lower activation of T cells in the spleen compared to the control mice in CLP, suggesting that iGC is immunomodulatory in sepsis. Low-dose GC supplementation significantly improved the survival of SR-BI-/- mice in CLP, but did not increase the survival rate of SR-BI+/+ mice in CLP, indicating that GC supplementation improves the survival specifically in mice with adrenal insufficiency. Overall, we revealed that iGC is essential for sepsis survival. iGC prevents kidney damage, modulates inflammatory responses and exerts immunomodulatory functions in sepsis. GC supplementation specifically improves survival of individuals with adrenal insufficiency in sepsis.

BACKGROUND: Sepsis is a clinical syndrome characterised by the systemic response to infection. It is a common problem in modern intensive care units and is associated with significant morbidity and mortality. Though the underlying cause of death is often multifactorial, refractory hypotension and cardiovascular collapse are frequently observed in the terminal phases of the condition. The aetiology of these cardiovascular abnormalities is complex but appears to be mediated by a circulating factor(s). The impact of sepsis upon left ventricular systolic function has been studied extensively. This may be because it is more readily assessed than diastolic function. Despite being increasingly appreciated as a contributor to morbidity and mortality in other clinical settings, there are scant data regarding the evaluation of left ventricular diastolic function in sepsis. Review of the haemodynamic monitoring literature reveals that many conventional measures of left ventricular filling, intravascular volume status and fluid responsiveness are influenced by ventricular diastolic (dys)function, such that interpretation can be challenging in critical care settings. In addition, many available techniques, such as pulmonary artery catheterisation, are invasive and potentially associated with risk to the patient. More robust and less invasive measures of left ventricular diastolic function and filling that can be applied within the intensive care unit (ICU) must be developed. The use of cardiac biomarkers, such as B-type natriuretic peptide (BNP), might represent a novel approach to evaluating left ventricular diastolic function and filling. BNP is released by the myocardium in response to wall stretch/tension. It has demonstrated value in the emergency department diagnosis of heart failure but interpretation of plasma BNP concentrations in critical care remains problematic. At least in part, this appears to relate to the significant number of potential confounders in patients with critical illness. Associations between BNP concentration and diastolic function have not previously been evaluated in severe sepsis and septic shock. The overall aim of this thesis is to investigate the usefulness of plasma BNP concentration in the evaluation of left ventricular diastolic function (including ventricular filling) in severe sepsis and septic shock. DIASTOLIC (DYS)FUNCTION IN SEPSIS: Review of the literature reveals that sepsis is associated with a spectrum of diastolic dysfunction. Characterisation of diastolic function in sepsis is challenging. In this regard, tissue Doppler imaging (TDI), offers promise. TDI is an echocardiographic technique that measures myocardial velocities, which are low frequency, high-amplitude signals filtered from conventional Doppler imaging. TDI has gained acceptance amongst cardiologists in the evaluation of diastolic function, particularly as a measure of ventricular relaxation and ventricular filling pressure; however, there are scant data regarding its use in critical care. We analysed echocardiographs from a large heterogeneous cohort of consecutive ICU patients (n=94) who had TDI as part of their clinically requested echocardiography. As well as supporting the feasibility of TDI in critically ill and mechanically ventilated patients, we demonstrated a wide range of TDI variables and a high prevalence of diastolic dysfunction using this modality. RODENT MODELS OF SEPSIS: We also sought to adapt, refine and evaluate rodent models of sepsis. Such models would allow control for a multitude of potential confounders commonly encountered in clinical sepsis. Two commonly employed rodent models of sepsis include caecal ligation and perforation (CLP) and endotoxin infusion. Comparison between CLP, sham and control groups demonstrated no difference in TDI or BNP. The observed changes in echocardiographic diastolic variables did not reflect those expected in sepsis and may be best explained by increases in heart rate rather than diastolic dysfunction per se. Endotoxaemia was associated with changes consistent with impaired myocardial relaxation (TDI) and reversible myocardial injury (histopathology), as expected in sepsis. BNP did not change significantly from baseline. This might be explained by the potential influence of fluid management upon BNP secretion. CLINICAL RESEARCH: The prediction of fluid responsiveness potentially prevents ineffective, excessive or deleterious intravenous fluid administration. Prospective evaluation of plasma BNP concentration in patients with septic shock found that it was not a predictor of a fluid responsive state. Furthermore, elevated BNP did not rule out a favourable response and therefore does not contraindicate a fluid challenge. Both impaired diastolic dysfunction, especially E/e’, and elevated BNP, have been associated with excess mortality in a range of cardiovascular diseases. These have not previously been compared in septic shock. In a cohort of patients with septic shock, E/e’ was a stronger predictor of mortality than cardiac biomarkers, including BNP. Fluid balance was an independent predictor of BNP in septic shock. OVERALL CONCLUSION: BNP appears not to be clinically useful in the evaluation of ventricular filling or diastolic function in sepsis. The association with fluid balance is a new finding and should be evaluated in a wider range of critically ill patients. In contrast to BNP, TDI appears to be a promising bedside tool in the evaluation of diastolic function and should be further evaluated in critical care.