Diagnosis and management of heart failure from hospital admission to discharge: A practical expert guidance.

Heart failure (HF) has high event rates, mortality, and is challenging to manage in clinical practice. Clinical management is complicated by complex therapeutic strategies in a population with a high prevalence of comorbidity and general frailty. In the last four years, an abundance of research has become available to support multidisciplinary management of heart failure from within the hospital through to discharge and primary care as well as supporting diagnosis and comorbidity management. Within the hospital setting, recent evidence supports sacubitril-valsartan combination in frail, deteriorating or de novo patients with LVEF≤40%. Furthermore, new strategies such as SGLT2 inhibitors and vericiguat provide further benefit for patients with decompensating HF. Studies with tafamidis report major clinical benefits specifically for patients with ATTR cardiac amyloidosis, a remaining underdiagnosed and undertreated disease. New evidence for medical interventions supports his bundle pacing to reduce QRS width and improve haemodynamics as well as ICD defibrillation for non-ischemic cardiomyopathy. The Mitraclip reduces hospitalisations and mortality in patients with symptomatic, secondary mitral regurgitation and ablation reduces mortality and hospitalisations in patients with paroxysmal and persistent atrial fibrillation. In end-stage HF, the 2018 French Heart Allocation policy should improve access to heart transplants for stable, ambulatory patients and, mechanical circulatory support should be considered to avoid deteriorating on the waiting list. In the community, new evidence supports that improving discharge education, treatment and patient support improves outcomes. The authors believe that this review fills the gap between the guidelines and clinical practice and provides practical recommendations to improve HF management.

Predictors of mitral annulus enlargement? A real-time three-dimensional transesophageal study.

BACKGROUND: Mitral annulus (MA) enlargement can be observed in various cardiac conditions but respective influence of left atrial (LA) and left ventricle (LV) size remained unclear. METHODS: In 120 patients who underwent a clinically indicated 3D-transesophageal-echocardiography, 30 atrial fibrillation (AF), 30 secondary mitral regurgitation (SMR), 30 primary myxomatous mitral regurgitation (PMR) and 30 mitral stenosis (MS), we evaluated the association between MA area (MA-area) and LA volume (LAvol) measured using the biplane area-length method, end-diastolic (LVEDV) and end-systolic (LVESV) volumes measured using the biplane Simpson method. MA-area was measured based on 3D datasets using QLab10. RESULTS: MA-area was correlated to LVEDV (r = 0.42, p < 0.0001), LVESV (r = 0.29, p = 0.001) but more markedly to LAvol (r = 0.62, p < 0.0001). Correlation between MA-area and LAvol was sustained in all subsets whereas MA-area was not correlated to LVEDV and LVESV in patients with SMR and with PMR (all p > 0.10). In multivariate analysis main predictors of MA-area were LAvol (p < 0.0001) and myxomatous etiology of MR (p = 0.0003) followed by LVEDV (p = 0.006) and LVESV (p = 0.02). CONCLUSION: In a population of patients with a wide range of LA/LV size related to various conditions, LA volume and myxomatous MR etiology appeared as main predictors of MA size whereas LV size had a more modest influence.

The expression of lysyl-oxidase gene family members in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are malignant disorders originating from clonal expansion of a single neoplastic stem cell and characteristically show an increase in bone marrow reticulin fibers. Lysyl oxidases (LOXs) are copper-dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin. Expression of LOX gene family members is increased in disorders associated with increased fibrosis. To evaluate involvement of LOX gene family in various MPNs. In-situ hybridization was used to detect Lysyl-Oxidase family members in bone marrow biopsies from patients with different MPNs. We compared normal bone marrows and those from patients with polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, and primary myelofibrosis (PMF). Serum levels of lysyl-oxidase from patients with PMF and healthy controls were also examined. LOX gene family was not detected in normal bone marrows. All members of the LOX gene family were over expressed in PMF. In other MPNs a differential pattern of expression was observed. Differences in gene expression were statistically significant (P < 0.010). The medianserum LOX levels in normal controls was 28.4 ± 2.5 ng\ml and 44.6 ± 9.44 ng\ml in PMF (P = 0.02). The varying pattern of expression of LOX genes may reflect differences in the pathophysiology of bone marrow fibrosis in these MPNs. These observations could be used as the basis for future targeted therapy directed against bone marrow fibrosis.

Neuropilins and semaphorins - from angiogenesis to autoimmunity.

Angiogenesis, the growth of new blood vessels from preexisting ones, is an important process in health and disease. The persistence of neovascularization in inflammatory diseases, such as rheumatoid arthritis (RA), might facilitate the entrance of inflammatory cells into the synovium and stimulate pannus formation. Several potent pro-angiogenic cytokines have been implicated in inflammatory angiogenesis. Of these, vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have been demonstrated to play a central role in RA, systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Increased serum levels of VEGF were found to correlate with disease activity and severity of these diseases whereas, remission was associated with decreased levels. In the last few years, other molecules, initially found in neurodevelopment, were found to be involved in angiogenesis and recently also in the immune system and autoimmunity. Neuropilins (NPs) are VEGF receptors, while some of the semaphorins (SEMAs) are neuropilins' ligands. Their involvement in the development of autoimmune diseases and the various mechanisms by which they may induce autoimmunity will be discussed in this review.

[Spontaneous idiopathic chylopericardium in childhood]. / Chylopericarde idiopathique spontané de l'enfant.

Here we report a case of a primary idiopathic chylopericardium in a 13 years old child. Pericardial effusion was diagnosed because the child suffered chest pain and fatigue. Pericardial drainage was performed and 800mL of chylous fluid was evacuated. Extensive investigations were performed but no cause could be found. Thoracic CT scan, lymphoscintigraphy and MRI did not evidence any communication between the thoracic duct and pericardium. After 2 recurrences of pericardial effusion while the child was on a medium chain triglycerides regimen, it was decided to ligate the thoracic duct and to do a partial pericardectomy. The result was excellent with complete resolution of the pericardial effusion and no recurrence since 3 years.

A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics.

Gray platelet syndrome (GPS) is a disorder characterized by thrombocytopenia and large platelets that lack alpha granules and their contents. We describe two siblings with GPS who are members of a Moslem Bedouin genetic isolate. The children, an 8-year-old girl and a 5-year-old boy, had characteristic pale blue platelets lacking alpha granules on electron microscopy. Platelet aggregation studies were normal. The girl underwent a bone marrow aspiration and biopsy which showed mild myelofibrosis and extensive emperipolesis, i.e., the passage of other hematopoietic cells through megakaryocytes. Both children lacked high-molecular-weight multimers of von Willebrand factor (vWF) and had reduced activity and antigens of vWf. Platelet activation was approximately normal when ADP was employed as agonist, but significantly impaired using the thrombin receptor-activating peptide (TRAP). These findings are explained in light of the mechanism of action of each agonist. In addition, we propose that the emperipolesis was caused by increased P-selectin in megakaryocytes, and resulted in release of fibroblastic growth factors, explaining the myelofibrosis. The detailed description of these cases provides a basis for future differentiation of the various types of GPS, and for our current attempts to isolate the gene causing GPS in this genetic isolate.

Effect of ozone on neutrophil function in vitro.

The application of ozone is widely practised as a form of alternative medicine, particularly in Germany and Eastern Europe. Ozone major autohemotherapy (the return of a small amount of a patient's blood to the circulation after ex vivo exposure to ozone) has been reported to have a therapeutic effect in various pathological conditions, including ischemic, infectious, autoimmune and neoplastic disorders. Ozone has an effect on the expression of cytokines, adhesion molecules and acute phase reactants, which are responsible in part for the respiratory inflammatory response observed after exposure to this gas. The purpose of the present study was to investigate the effect of ozone administration ex vivo, at a concentration commonly used in major autohemotherapy, on peripheral blood neutrophil function in vitro. Blood drawn from healthy volunteers was studied for neutrophil adhesion, chemotaxis and O-2 production before and after exposure to 30 microg/ml ozone. There was no significant difference in adhesion and chemotaxis of neutrophils exposed to ozone versus unexposed cells. O-2 production was minimally decreased (20.3 +/- 5.0 vs. 22.1 +/- 5.5 nmol/106 cells/10 min, respectively; P=0.01), a reduction of no clinical significance. This study confirms that major autohemotherapy with ozone is safe as far as neutrophil function is concerned. Combined with previous data, it seems that well-designed clinical trials to assess the efficacy of major autohemotherapy would pose no danger to blood cell populations, and should be encouraged.

The role of high-dose oral iron supplementation during erythropoietin therapy for anemia of prematurity.

OBJECTIVE: To assess whether a high intake of oral iron would increase the effect of recombinant human erythropoietin (rHuEPO) on hemoglobin synthesis. METHODS: We studied 30 preterm infants (gestational age 29+/-1.8 weeks, birth weight 1161+/-200 g, at age of 28+/-10 days) who were randomly assigned to receive either 8 mg/kg per day (n=15) or 16 mg/kg per day of oral iron during a course of rHuEPO therapy (900 microg/kg per week) for a duration of 4 weeks. Both groups were comparable in regard to clinical and laboratory data at the time of enrollment. RESULTS: rHuEPO caused a significant increase in reticulocyte count in the low- and high-dose iron groups, 17.1+/-5.3 to 34.7+/-9.2 and 16.3+/-3.3 to 42.5+/-5.6 (10(9)/l), respectively (p<0.05). However, in both groups, hematocrit values remained stable at the end of the study as compared to baseline (0.35+/-0.03% vs. 0.30+/-0.03%, 0.35+/-0.05% vs. 0.30+/-0.03%, NS) and in both groups there was a comparable and significant decrease in ferritin level (259+/-109 to 101+/-40 and 168+/-54 to 69+/-38 microg/l, respectively; p<0.01). The rates of bloody stools without any evidence of necrotizing enterocolitis were not significantly different between the two treatment groups (1/15 vs. 4/15, NS). CONCLUSION: We conclude that a higher dose (16 mg/kg per day) of oral iron is not more beneficial when compared to a lower dose (8 mg/kg per day) during rHuEPO therapy for anemia of prematurity. Further studies will define the optimal dosage and route of administration of iron supplementation during rHuEPO therapy.

The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection.

The mechanism of lymphomagenesis of hepatitis C virus (HCV)-related B-cell lymphoma is unknown. Recently, it has been suggested that HCV may induce B-cell clonal proliferation and t(14;18) translocation in patients chronically infected with the virus. Thus, this study investigated the effect of antiviral treatment on immunoglobulin heavy-chain gene (IgH) rearrangement and t(14;18) translocation in HCV infected patients. Twenty-nine patients with chronic HCV infection were studied in whom IgH rearrangement and/or t(14;18) translocation were previously detected. The IgH rearrangement (FR3/JH) and t(14;18) translocation (MBR bcl2-JH) were detected in peripheral blood mononuclear cells by polymerase chain reaction. Fifteen of 29 patients (8 with IgH rearrangement, 6 with t(14;18) translocation, and 1 with both) were treated with either interferon-alpha or by combination therapy with interferon and ribavirin for 6 to 12 months. IgH rearrangement became negative in 7 of 9 treated patients compared with only 1 of 8 of nontreated patients (P <.02). The t(14;18) translocation became negative in 6 of 7 treated patients compared with 1 of 6 nontreated patients (P =.03). Disappearance of IgH rearrangement or t(14;18) translocation was strongly associated with virologic response to treatment. Two t(14;18)+ patients developed B-cell lymphoma during follow-up. Antiviral treatment appears to be effective in eliminating the clonal proliferation of B cells in patients with chronic HCV infection and may prevent the subsequent development of lymphoma. The mechanism can be related to a direct effect of interferon-alpha on the proliferating clone or to an indirect effect by eradicating the antigenic stimulus.

bcl-2 and immunoglobulin gene rearrangement in patients with hepatitis C virus infection.

An association between chronic hepatitis C virus (HCV) infection and clonal proliferation of B cells, including B cell lymphoma, has recently been demonstrated. However, the mechanism of malignant transformation is still unknown. It has been shown that B cells from patients with type II mixed cryoglobulinaemia (MC), strongly express the antiapoptotic bcl-2 oncogene product. Therefore, we investigated a possible mechanism of lymphomagenesis, the occurrence of bcl-2 and immunoglobulin gene rearrangement (IgH) in HCV-infected patients. Three groups of patients were studied: (1) 44 patients with HCV and MC (anti-HCV and HCV RNA positive); (2) 59 patients with chronic HCV infection without MC; (3) 50 patients with chronic liver disease (CLD) not related to HCV infection. The t(14;18) translocation (MBR bcl-2-JH) and IgH rearrangement (FR3/JH) were detected by polymerase chain reaction (PCR) in peripheral mononuclear cells. bcl-2 translocation was detected in 17/44 (39%), 7/59 (12%) and in none of the patients of groups 1, 2 and 3 respectively (P < 0.01). Monoclonal IgH rearrangement was detected in 15/44 (34%), 5/59 (8.5%) and 2/50 (4%) patients of groups 1, 2 and 3 respectively (P < 0.05). HCV-infected patients had a higher prevalence of monoclonal IgH rearrangement and bcl-2 translocation than patients with CLD of other aetiologies. These data suggest that HCV may play a role in the multistep mechanism of lymphomagenesis by inducing clonal proliferation of B cells and inhibition of apoptosis.

Amplification of immunological functions by subcutaneous injection of intermediate-high dose interleukin-2 for 2 years after autologous stem cell transplantation in children with stage IV neuroblastoma.

BACKGROUND: Immunotherapy given post-autologous stem cell transplantation may eliminate residual tumor cells escaping the conditioning protocol. METHODS: Five children suffering from stage IV neuroblastoma were treated by recombinant interleukin-2 (IL-2) post-autologous peripheral blood stem cell transplantation. The patients' peripheral mononuclear cells were monitored for CD3+ and CD56+ levels, their proliferative response and killing of various cell lines targets. RESULTS: An increase in the level of total lymphocytes, mainly due to expansion of T cells, and enhanced proliferative response to phytohemaglutinin were observed. Elevated cytotoxicity against K562 and neuroblastoma target cells was detected in four patients and against K562 targets in one patient. Toxicity included mild thrombocytopenia, and fever in four patients and mild to moderate encephalopathy which necessitated withdrawing one patient from the protocol. Three of five patients studied are alive today, one of them whose IL-2 was stopped, is in relapse. Two patients have died. CONCLUSIONS: Immunotherapy with s.c. intermediate-high dose IL-2 is feasible and results in expansion of T cells and in stimulation of killing activity against several targets including in some cases, neuroblastoma tumor cells.

Computer-assisted image analysis can aid the prognostication of advanced-stage neuroblastomas.

PURPOSE: The aim of this work was to detect nuclear parameters related to the prognosis of patients with stage III, IV or DS neuroblastomas. METHODS: Histological sections of 25 operation specimens obtained from children with advanced-stage neuroblastomas were subjected to computer-assisted image analysis. Statistical relationships between nuclear descriptors of the tumor cells and patients' clinical outcome were determined. RESULTS: The coefficient of variability of the mean nuclear area the mean nuclear elongation factor, and the mean nuclear averaged Feret diameter of the neuroblastoma cells were ascertained to be discriminators separating high-grade from low-grade tumors. CONCLUSIONS: The histomorphometrically gauged nuclear parameters may help oncologists to assess the prognosis of patients with advanced-stage neuroblastoma.

Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia: the Israel National Study report.

BACKGROUND: Preventive cranial radiotherapy (CRT) in childhood acute lymphoblastic leukemia (ALL), although effective, may be associated with neurologic sequelae and second malignancies. Attempts to replace CRT with intensified intrathecal therapy (IT) have shown promise in lower risk subgroups. In the Israel National Study (INS) 89 trial, the efficacy of extended triple IT (TIT) alone for cranial prophylaxis in an enlarged non-high risk group (Non-HRG) was assessed in the context of a modified ALL-Berlin-Frankfurt-Munster (BFM) systemic chemotherapy program. METHODS: Non-HRG patients included the standard-risk group (SRG) and the risk group (RG), as defined in ALL-BFM 86. In the INS 89 protocol, all Non-HRG patients were treated with extended TIT x 18 times and systemic therapy based on the BFM 86 protocol, with the addition of etoposide x 4 times. The HRG patients, classified according to BFM 86 criteria, were treated with the BFM 90 HRG protocol including CRT. RESULTS: A total of 250 patients were enrolled. At a median follow-up of 58 months (range, 2-8.5 years), the overall 5-year event free survival (EFS) was 73.5% +/- 3% (standard error ¿SE), and the cumulative central nervous system (CNS) recurrence rate was 4.3% +/- 1.4% (SE) (isolated, 2.3%; combined, 2%). Of the 220 eligible children, 189 (86%) were in the Non-HRG group, and their 5-year EFS was 77.8% +/- 3% (SE). The cumulative CNS recurrence rate for patients without CNS disease at presentation was 3.1% +/- 1% (SE) (isolated, 1.7%; combined, 1.4%). Within the risk subsets defined by the BFM 86 of the Non-HRG, the 5-year EFS rates of the RG (148 patients) and the SRG (41 patients) were 74.8% +/- 4% (SE) and 89.5% +/- 5% (SE), respectively, and the rates of CNS recurrence (isolated and combined) were 4% and 0%, respectively. For the HRG (31 patients), the 5-year EFS and CNS recurrence rates were 47.9% +/- 9% (SE) and 8. 5% +/- 6% (SE), respectively. CONCLUSIONS: Early extended TIT therapy in the context of modified BFM 86 systemic chemotherapy was found to provide adequate CNS protection and systemic leukemia control in patients with non-high risk ALL. However, no benefit for etoposide could be proven in this study.

T-cell chronic lymphocytic leukaemia with pulmonary involvement and relapsing BOOP.

We report on a case of T-cell chronic lymphocytic leukaemia involving the lung, with clinical, radiological and histological evidence of relapsing bronchiolitis obliterans-organizing pneumonia in a 70-yr-old female. Pulmonary disease was the major clinical manifestation of this chronic lymphocytic leukaemia. The first two episodes of the patient's pulmonary disorder resolved without treatment, and the third episode was treated with cytotoxic agents as part of the leukaemia treatment regimen. Two additional episodes of the pulmonary disorder occurred; both responded to prednisone.

Effect of hydroxyurea in sickle cell anemia: a clinical trial in children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia.

This study evaluated the efficacy of hydroxyurea treatment in the prevention of vaso-occlusive crises among children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia. Nineteen children and young adults with severe sickle cell disease were enrolled to the hydroxyurea treatment trial. The incidence of vaso-occlusive crises, acute chest syndrome, hemolytic crises, splenic sequestration episodes, blood transfusions, and hospital days in the 2 years before hydroxyurea (HU) treatment were compared with the same parameters in the first 2 years of treatment. The patients received a mean dose of 21.3 mg/kg/day daily and were treated during a mean period of 40.3 +/- 14 months (range 20 to 68 months). Significant increases were observed after 1 month in the Hgb, MCV, MCH, and MCHC levels and were more notable after 3 months. The increase in the Hgb F level became important after 3 months of HU therapy and was highly significant (p < .001) beyond 6 months. No differences were observed in the RDW, reticulocyte count, Hgb S, and Hgb A2. Severe neutropenia was observed in one case. A decrease in the frequency of vaso-occlusive crises, acute chest syndrome, hemolytic crises, blood transfusions, and days spent in the hospital was demonstrated during the HU treatment period compared to the same period before. The clinical and laboratory response to HU was dramatic in severely affected sickle cell anemia (SCA) patients. The response to HU in children and teenagers with severe sickle cell anemia is similar to the response in adults, and no severe adverse effects were observed.

Familial hemophagocytic lymphohistiocytosis: improved neurodevelopmental outcome after bone marrow transplantation.

A child with familial hemophagocytic lymphohistiocytosis (HLH) underwent allogeneic bone marrow transplantation (BMT) at age 5 months. At that time he showed delayed psychomotor development, and computed tomography revealed diffuse calcification. After BMT, a gradual neurodevelopmental normalization was observed. The potential ability of BMT to reverse neurodevelopmental deterioration in HLH should be considered.

Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity.

Erythropoietin (rHuEPO) therapy has been shown to be beneficial in preventing and treating anaemia of prematurity and to decrease the need for blood transfusions. There is, however, only scanty data on the effect of rHuEPO therapy on iron metabolism. We studied 29 preterm infants (age 34 +/- 14 days) who were randomly assigned to receive either rHuEPO 900 U kg-1 week-1 with 6 mg kg-1 day-1 of iron for 4 weeks (n = 15) or no therapy. The following parameters were evaluated and compared between and within groups at the beginning, during and at the end of the study: Haematocrit (SI), reticulocytes (10(9) micrograms l-1), serum ferritin (microgram 1-1) and iron (mumol l-1). The results were as follows. At the baseline, erythropoietin levels were similar in both groups: 7.2 +/- 5.6 versus 6.2 +/- 3.2 mU ml-1 (NS). In the treated infants the haematocrit remained stable during the study and was significantly higher than in the control group by the end of the study: 0.34 +/- 0.03 versus 0.28 +/- 0.05 (p = 0.001). rHuEPO therapy increased the reticulocyte count from 130 +/- 70 to 430 +/- 200 (p = 0.0002). However, rHuEPO therapy depleted both serum ferritin and iron levels from 321 +/- 191 to 76 +/- 58 micrograms l-1 (p = 0.04) and from 18 +/- 5 to 13 +/- 4 mumol l-1 (p = 0.03), respectively. We conclude that rHuEPO therapy prevented anaemia and its sequelae; however, serum ferritin and iron levels were depleted. We suggest that the effect of rHuEPO may be further increased by higher iron supplementation.