BACKGROUND:Anemia is common in heart failure (HF), but there is controversy regarding its contribution to morbidity and mortality.OBJECTIVE:To examine the association of mild and severe anemia with acute HF severity and mortality.METHODS:Data were prospectively collected for patients admitted to all departments of medicine and cardiology throughout the country during 2 months in 2003 as part of the Heart Failure Survey in Israel. Anemia was defined as hemoglobin (Hb) < 12 g/dl for women and < 13 g/dl for men; Hb < 10 g/dl was considered severe anemia. Mortality data were obtained from the Israel population registry. Median follow-up was 33.6 months.RESULTS:Of 4102 HF patients, 2332 had acute HF and available hemoglobin data. Anemia was common (55%) and correlated with worse baseline HF. Most signs and symptoms of acute HF were similar among all groups, but mortality was greater in anemic patients. Mortality rates at 6 months were 14.9%, 23.7% and 26.3% for patients with no anemia, mild anemia and severe anemia, respectively (P < 0.0001), and 22.2%, 33.6% and 39.9% at one year, respectively (P < 0.0001). Compared to patients without anemia, multivariable adjusted hazard ratio was 1.35 for mild anemia and 1.50 for severe anemia (95% confidence interval 1.20-1.52 and 1.27-1.77 respectively).CONCLUSIONS:Anemia is common in patients with acuteHF and is associated with increased mortality correlated with the degree of anemia.

The objective of this study was to examine whether treatment with recombinant human erythropoietin (rHuEPO), previously found to be associated with a positive effect on cell-mediated immunity and humoral immunity (hepatitis B vaccine), is associated with an improved response to the seasonal influenza (flu) vaccine. Three groups received flu vaccine: healthy controls, hematologic patients not treated with rHuEPO ("No EPO" group), and hematologic patients receiving rHuEPO for their anemia ("EPO" group). Anti-flu Ab titer was measured (complement fixation test) from blood samples drawn before and approximately 3-4 weeks, 7-8 weeks and 4 months after vaccination. Nineteen healthy subjects were compared with 17 No EPO and 17 EPO patients. Mean ages were 59.5, 61.3, and 73.1 years, respectively (EPO patients were older; p = 0.005). In the healthy group, the percentage of those sustaining only a partial (twofold) response, a strong (fourfold or greater) response, and an overall response (combined partial and strong responses) were 31.6%, 57.9%, and 89.5%, respectively. In the No EPO group, values were 35.3%, 17.6%, and 52.9%, respectively. EPO group results were similar to those of the healthy controls: 23.5%, 58.8%, and 82.4% (p = 0.016, EPO vs. No EPO). In conclusion, hematologic patients (NoEPO group) respond poorly to the flu vaccine, compared with healthy subjects, and rHuEPO treatment is associated with an improved immune response to the flu vaccine in hematologic patients, with titers similar to those of healthy subjects.

Erythropoiesis stimulating agents (ESAs) have been used widely for anemic patients, especially those on dialysis and with cancer. However, reports have suggested shorter survival in erythropoietin (EPO)-treated cancer patients. The purpose of this review is to summarize and evaluate critically the current information about ESA treatment and its possible association with mortality in cancer patients. The pendulum that initially swung in the direction of widespread ESA treatment, and then in the direction of no treatment, is swinging back toward a stable position. This review also provides tools to decide how and when to use ESAs safely, according to accepted guidelines.

Abstract Abstract 4793 Introduction: Erythropoietin (EPO) is the major hormone which enhances proliferation and maturation of the red cell lineage, and its recombinant form (rHuEPO) is used extensively to treat various types of anemia. rHuEPO has also been found to exert effects in other organ systems, and our previous work has demonstrated an immunomodulatory role for EPO. Recently, we have also found that mice exposed to high levels of EPO (either rHuEPO injections or transgenic mice overexpressing human EPO), have significantly lower levels of blood glucose than those of their respective controls (Katz et al., J Endocrinol 2010;205:87-95). The current retrospective study was designed to determine whether rHuEPO treatment in hematologic patients, is associated with decreased blood glucose levels. Methods: Patients receiving rHuEPO were examined, comparing glucose levels (morning blood tests, assumed to be fasting) while on rHuEPO treatment to those off treatment. All patients served as their own controls. To test the association between rHuEPO treatment and blood glucose levels, we employed a mixed-model repeated-measures analysis of variance (ANOVA). Results: The charts of 19 patients were reviewed to determine the starting date of rHuEPO and the levels of blood glucose in relation to rHuEPO treatment. Mean age: 77 (range: 54–93). Thirteen patients had myelodysplastic syndrome, and six had multiple myeloma. Two patients had diabetes mellitus. Average glucose levels (mean±95%CI) without rHuEPO treatment were 116.07±4.98. Glucose measurements were available for a median of 9.23 (interquartile range: 7.90–16.80) months after the initiation of rHuEPO treatment. The average glucose level over that period of time was 101.77±4.86 (p<0.0001). The two diabetic patients also demonstrated a trend towards reduced serum blood glucose and lower HbA1C while being treated with rHuEPO. Conclusions: Treatment of hematologic patients with rHuEPO is associated with significantly lower blood glucose levels, and might serve in the future to improve glucose control in anemic patients with hyperglycemia. Further studies with both diabetic and non-diabetic patients are currently underway to clarify this association. Disclosures: No relevant conflicts of interest to declare.

Most patients with myelodysplastic syndrome (MDS) are classified at diagnosis as having a low/INT-I or INT-II/high risk disease, based on the classical International Prognostic Scoring System (IPSS) criteria. The low/INT-I risk patients are usually managed mildly with supportive care, including red blood cell (RBC) transfusions, erythroid stimulating agents (ESAs), other cytokines (G-CSF, platelet stimulating agents), as well as thalidomide and lenalidomide. Some patients receive immunosuppressive therapy, and iron chelation is indicated in iron overloaded patients. Aggressive approach (hypomethylating agents, chemotherapy and stem cell transplantation) is usually not applied in such patients. Occasionally, we observe a "low risk" patient with rapid progression of disease and poor outcome. Can we identify demographic, clinical, laboratory, cellular-biological and/or molecular parameters that can predict "poor prognostic features" (PPF) in "low risk" MDS patients? Clinical and laboratory parameters have been reported to be associated with poor prognosis, in addition to the known "classical" IPSS criteria. These include older age, male gender, poor performance status, co-morbidities, degree of anemia, low absolute neutrophile count (ANC) and platelet counts, RBC transfusion requirements, high serum ferritin, high LDH, bone marrow (BM) fibrosis, increased number of BM CD34+ cells and multi-lineage dysplasia. Certain immunophenotypes (low CD11b, high HLA-Dr, CD34, CD13 and CD45), clonal granulocytes, multiple chromosomal abnormalities, chromosomal instability, short telomeres and high telomerase activity were also reported as PPF. Studies of apoptosis identified Bcl-2 expression and high caspase 3 as PPF, while the reports on survivin expression have been confusing. Recent exciting data suggest that methylation of p15 INK4b and of CTNNA1 (in 5q-), high level of methylation of other genes, absence of the TET2 mutation, down regulation of the lymphoid enhancer binding factor 1 (LEF1), mutation of the polycomb-associated gene ASXL1 and a specific 6-gene signature in gene expression profiling - are all associated with poor prognosis in MDS. Do we have data suggesting a different treatment for "low risk" MDS patients displaying PPF? Two teams, the combined Nordic-Italian and the GFM groups have reported an improved survival with ESAs. The GFM has achieved prolonged survival with iron chelation. Recently, encouraging data with survival advantage in azacitidine-treated patients have been published, including a few INT-I patients. Finally, data suggest that low/INT-I MDS patients who undergo stem cell transplantation (SCT0 do better than INT-II/high risk patients). In summary, some patients, classified as "low risk MDS" carry PPF. An appropriate therapeutic approach is indicated. Future updated classifications and prospective trials may lead to a better outcome.

Anemia has been recognized as a risk as well as a precipitating factor in ischemic heart disease, and in congestive heart failure (CHF). However, there are still open questions regarding the prevalence of anemia in CHF, and the severity and associated clinical manifestations of the anemic CHF patient. In order to characterize CHF in Israel, a national survey was conducted during the period March 1–April 30, 2004. Data were collected on all patients with CHF exacerbation admitted to 96 departments of medicine and 26 cardiology units throughout the country. In this study we have focused on anemia in CHF patients with a special emphasis on the differences observed between CHF patients with anemia (A group) and CHF patients with no anemia (NA group).

Recombinant human erythropoietin (rHuEPO) originally used to treat anemia has also been found to have several pleiotropic actions, e.g. neuroprotection, cardioprotection, and immune effects. Based on our preliminary data in mice, and on the studies by others of reduced insulin resistance in rHuEPO-treated hemodialysis patients, we have raised the question of a potential association between EPO and glycemic control. Here we report our observation of glucose control in four rHuEPO-treated diabetic patients. These diabetic patients were treated with rHuEPO for their anemia associated with chronic renal failure (CRF) or myelodysplastic syndrome (MDS). We retrospectively compared the available clinical parameters reflecting blood glucose control before and after initiation of EPO therapy. The parameters included fasting glucose levels, hemoglobin A1C (HbA1C), and medication requirements. The data are presented in the Table; where no number is provided, the data were unavailable or incomplete. The number of measurements available in each patient varied: For glucose-level, patient 1 had 10 measurements over the 3 months before (pre-rHuEPO) and 6 over the 3 months after rHuEPO initiation (post-rHuEPO). Patient 2 had more than 50 measurements, both over 3 years pre-rHuEPO and 2 years post-rHuEPO; patient 3 had more than 50 in 3 years pre-rHuEPO, but only 12 in 2 years post-rHuEPO, while patient 4 had more than 50 measurements, both over 3 months pre-rHuEPO and 3 months post-rHuEPO. HbA1C: Patient 2 had 10 measurements pre-rHuEPO, and 6 post-rHuEPO; Patient 3 had 10 pre-rHuEPO and 10 post-rHuEPO, patient 4 had none. Patient 1 had only 2 measurements of HbA1c (7.7 pre-rHuEPO; 6.3 post-rHuEPO). Statistical significance (p<0.05) was computed using the two-tailed unpaired student’s t test; a diamond (♦) represents a statistically significant difference. The Table shows that in all four patients, glucose control improved following the initiation of rHuEPO treatment. Of note, patient 1 was treated with unchanging doses of oral hypoglycemic therapy. Patient 2 was treated with increasing doses of insulin as is often seen in diabetes mellitus, a progressive disease. The increasing insulin requirement continued even after initiation of rHuEPO therapy, yet it appeared that this increase did not fully account for the significantly improved glycemic control. Note that the insulin requirements in patients 3 and 4 were reduced post-rHuEPO, yet due to the paucity of post-rHuEPO data, the lower glucose of patient 3 did not reach statistical significance. We conclude that rHuEPO may have an important clinical impact on the control of glucose in these patients. Future trials are currently underway to substantiate and unravel the molecular mechanism underlying this phenomenon. We are examining the effect of rHuEPO administration on glycemic control, and thus exploring the potential role of rHuEPO as part of the armamentarium in the treatment of diabetes. | | | Mean fasting glucose (mg/dl) | Mean HbA1C (%) | Average daily insulin (units) | |:-------:| --------- | ---------------------------- | ---------------- | ----------------------------- | ---------------- | | Patient | Diagnosis | Pre EPO therapy | Post EPO therapy | Pre EPO therapy | Post EPO therapy | Pre EPO therapy | Post EPO therapy | | 1 | MDS | 157 | 102♦ | \---| | \---| | \---| | \---| | | 2 | CRF | 202 | 126♦ | 8.3 | 6.6♦ | \---| | \---| | | 3 | CRF | 154 | 133 | 7.0 | 6.0♦ | 91 | 38♦ | | 4 | MDS | 137 | 123♦ | \---| | \---| | 21 | 14♦ | Glucose-associated parameters in EPO-treated patients

Recombinant human erythropoietin has become an essential part of the management of anemic patients with end-stage renal disease. It is also used to treat the anemia associated with cancer and other diseases, and it improves quality of life. In recent years, studies in animals and humans have focused on the use of rHuEPO for other indications. It has been found to play a role in both cardioprotection and neuroprotection. It has effects on the immune system, and can cause regression in hematologic diseases such as multiple myeloma. It may also improve the response of solid tumors to chemotherapy and radiation therapy. On the other hand, concerns have been raised following two studies of patients with solid tumors in whom those treated with rHuEPO had diminished survival. Criticism of the design of these studies makes it clear that large, well-designed, randomized trials must be performed to determine the role of rHuEPO in the treatment of cancer, and more generally to clarify the full clinical benefits of the drug, while minimizing the harm.

Erythropoietin (Epo) is being used to treat anemias. We have observed prolonged survival in patients with multiple myeloma (MM) on recombinant Epo (rHuEpo) (Mittelman, EJH 2004). Studies on mice suggested an Epo anti-MM immune effect (Mittelman, PNAS 2001; Katz, Acta Haem 2005), and we have also found improved immunity in rHuEpo-treated MM patients. Here we tested the effect of Epo on immune function in myelodysplastic syndrome (MDS). We tested 27 MDS patients (15 controls). We show immune defects in early (IPSS low/int1) MDS, that are more pronounced in progressive disease. Consistent with previous reports, and extending our analysis to other immunologic functions, we show that MDS patients have decreased lymphocyte counts, manifested mainly in reduced CD4+ T-cell percentage and reduced mononuclear cell (MNC) proliferation induced by phytohemagglutinin (PHA). In MDS, the basal function of both CD4+ and CD8+ T cells expressing the early activation marker CD69 was higher than in controls, but following PHA stimulation, the increment of these CD69+ cells was attenuated. MDS patients also had a decreased percentage of the CD4+ cells expressing the IL-2 receptor, CD25. Finally, in MDS the proportion of CD8+ T-cells expressing the co-stimulatory molecule CD28 was reduced. To test whether rHuEpo treatment had any effect on these parameters, we compared these functions in 14 MDS patients (early disease) on rHuEpo with 8 early MDS patients who were not on rHuEpo. The rHuEpo-treated group included 12 patients responding to rHuEpo (increased Hb; Epo-responders) and 3 patients who continued to require transfusions (Epo-non-responders). The results show a significant increase in PHA-mediated activation of both CD4+ and CD8+ T cells, and a tendency towards normalized CD4+ percentage. The non-responders also showed a tendency towards normalized T-cell percentage and number, but they did not show any augmented activation, or proliferation potential (Table, mean ± SE).

We describe an 80-year-old patient who developed Staphylococcus aureus septicemia several days after the implantation of a double stent in the proximal and mid-left anterior descending artery. The infection was complicated by multiple abscesses in the lungs and liver, as well as by bilateral bacterial endophthalmitis requiring right vitrectomy. Long-term antibiotic treatment was successful. Rarity notwithstanding, heightened awareness of this potential complication of a common cardiac procedure is important since diagnosis and immediate therapy are mandatory.

Professional meetings are an important way of educating, communicating and sharing updated information. After having attended dozens of medical and scientific meetings and conferences, the authors realized that many lectures are not appropriately presented due to a lack of proper speaking skills or inadequate facilities. Although the art of speaking is, to some degree, an inborn talent, speaking skills can be learned, exercised and put into practice. The current article summarizes the authors' thoughts and opinions about what makes a medical or scientific lecture a good or bad one, and it provides suggestions for improving a speaker's performance. Common mistakes are discussed, along with tips and recommendations on how to prepare and provide an interesting, professional, entertaining and attractive lecture. Guidelines are given on how to structure and balance a lecture. A special segment is devoted to speaker–audience relations. A detailed chapter emphasizes rules for preparing good slides. Finally, some recommendations are made regarding facilities in the lecture hall. The authors believe that if the proposed suggestions were applied, more presentations would be successful.

Inflammation has been demonstrated to be an important risk factor for the development of cardiovascular events. Patients with elevated white blood cell counts have been shown to be in a higher risk of developing acute myocardial infarction and acute coronary and vascular events. We review the clinical data of high white blood cell counts and the prognosis, and demonstrate several possible mechanisms. It is possible that measuring white blood cell count and subpopulations could be used for a better way of risk stratification of patients admitted with acute vascular events.

Preeclampsia is a common, pregnancy-specific syndrome defined by clinical findings of elevated blood pressure combined with proteinuria and edema. The incidence has been reported in 2±7% of all pregnancies. The clinical findings manifest late in pregnancy, usually after the 20th week of gestation. The disease can progress rapidly, at times without warning, to a life-threatening convulsive phase ± eclampsia. The pathologic changes in women dying with eclampsia are characterized by intense vasospasm, hypoperfusion and necrosis. Gross morphologic and histopathologic changes are observed in many organs including the heart, lungs, kidney, liver, brain and placenta, indicating that this syndrome is a multisystemic disease [1]. Generalized vasodilatation is the primary hemodynamic change in normal pregnancy and is already present during the luteal phase in women who subsequently become pregnant. In the 1980s, pregnancy-associated biological dominance of prostacyclin over thromboxane-A2 was thought to cause vascular refractoriness to vasoconstrictors and thus vasodilation. More recently, it was demonstrated that vasodilator prostaglandins do not mediate the attenuation of systemic and renal pressor responsiveness in pregnancy. Several peptide-regulatory factors (cytokines, binding proteins, growth factors) released in an appropriate steroid environment appear to play an integral part in this mediation, and nitric oxide may be important as a final messenger [2].