Clinical importance of risk factors and exercise testing for prediction of significant coronary artery stenosis in women recovering from unstable coronary artery disease: the Stockholm Female Coronary Risk Study

BACKGROUND: The objectives of this study were to investigate the relation between coronary risk factors, exercise testing parameters, and the presence of angiographically significant coronary artery disease (CAD) (> or =50% luminal stenosis) in female patients previously hospitalized for an acute CAD event. METHODS AND RESULTS: All women younger than age 66 years in the greater Stockholm area in Sweden who were hospitalized for acute coronary syndromes during a 3-year period were recruited. Besides collection of clinical parameters, coronary angiography and a symptom-limited exercise test were performed in 228 patients 3 to 6 months after the index hospitalization. The mean age was 56 +/- 7 years. Angiographically nonsignificant CAD (stenosis <50%) was verified in 37% of the patients; significant CAD was found in 63%. The clinical parameters that showed the strongest relation with the presence of significant CAD after adjusting for age were history of myocardial infarction (odds ratio [OR] 4.91, 95% confidence interval [CI] 2.35 to 7.49), history of diabetes mellitus (OR 3.83, 95% CI 1.63 to 14.31), serum high-density lipoprotein cholesterol <1.4 mmol/L (OR 2.11, 95% CI 1. 20 to 3.72), and waist-to-hip ratio >0.85 (OR 1.78, 95% CI 1.02 to 3. 10). A low exercise capacity and associated low change of rate-pressure product from rest to peak exercise were the only exercise testing parameters that were significantly related to angiographically verified significant CAD (<90% of the predicted maximal work capacity adjusted for age and weight, OR 1.91, 95% CI 1. 04 to 3.50). CONCLUSIONS: In female patients recovering from unstable CAD, exercise capacity was the only exercise testing parameter of value in the prediction of significant CAD. The consideration of certain clinical characteristics and coronary risk factors offer better or complementary information when deciding on further coronary assessment.     

Hematogones: a multiparameter analysis of bone marrow precursor cells

Morphologically distinct lymphoid cells with homogeneous, condensed chromatin and scant cytoplasm can be observed in large numbers in the bone marrow of children with a variety of hematologic and nonhematologic disorders. In some patients, these cells may account for greater than 50% of the bone marrow cells, creating a picture that can be confused with acute lymphoblastic leukemia (ALL) or metastatic tumor. Although originally called hematogones (HGs), a variety of other names have been proposed for these unique cells. The clinical significance of expanded HGs has not been resolved, and the biologic features of these cells are incompletely described. In this study, we correlate the clinical, morphologic, cytochemical, flow cytometric, molecular, and cytogenetic properties of bone marrow samples from 12 children with substantial numbers of HGs (range 8% to 55% of bone marrow cells). Diagnoses in these patients included anemia, four; neutropenia, one; anemia and neutropenia, one; idiopathic thrombocytopenic purpura, two; retinoblastoma, two; Ewing's sarcoma, one; and germ cell tumor, one. Flow cytometric analyses of bone marrow cells demonstrated a spectrum extending from early B-cell precursors (CD10+, CD19+, TdT+, HLA-Dr+) to mature surface immunoglobulin-bearing B cells in these patients, corroborating our morphologic impression of HGs, intermediate forms, and mature lymphocytes. DNA content was normal, and no clonal abnormality was identified by either cytogenetic or immunoglobulin and T-cell receptor (TCR) gene rearrangement studies. Follow-up ranged from 3 months to 3 years. None of the patients has developed acute leukemia or bone marrow involvement by solid tumor. The possible role of HGs in immune recovery and hematopoiesis is presented.     

Service utilization in a sample of preschool children with autism spectrum disorder: A Canadian snapshot

OBJECTIVE:

To describe services received by preschool children diagnosed with autism spectrum disorder (ASD) during the five-year period following their diagnosis.

METHOD:

An inception cohort of preschoolers diagnosed with ASD from Halifax (Nova Scotia), Montreal (Quebec), Hamilton (Ontario), Edmonton (Alberta) and Vancouver (British Columbia) were invited to participate. Parents/caregivers (n=414) described the services provided to their children at four time points: baseline (T1; within four months of diagnosis; mean age three years); six months later (T2); 12 months later (T3); and at school entry (T4). Data were first coded into 11 service types and subsequently combined into four broader categories (no services, behavioural, developmental and general) for analysis.

RESULTS:

More than 80% of children at T1, and almost 95% at T4 received some type of service, with a significant number receiving >1 type of service at each assessment point. At T1, the most common service was developmental (eg, speech-language therapy). Subsequently, the most common services were a combination of behavioural and developmental (eg, intensive therapy based on applied behaviour analysis and speech-language therapy). Service provision varied across provinces and over time.

DISCUSSION:

Although most preschool children with ASD residing in urban centres were able to access specialized services shortly after diagnosis, marked variation in services across provinces remains a concern.     

A technique for specific removal of factor IX alloantibodies from human plasma: partial characterization of the alloantibodies

A method for specific removal of large amounts of factor IX:C alloantibodies by a resin to which highly purified factor IX was linked (factor IX CH-Sepharose) is described. Factor IX was isolated from human plasma by a three-step procedure, including barium citrate adsorption and elution, DEAE-Sepharose CL-6B chromatography, and dextran sulfate agarose chromatography. Approximately 100 mg factor IX was obtained from 60 liters of plasma. The preparation was about 95% pure as judged by SDS-PAA gel electrophoresis. Its specific coagulant activity was 160 U/mg (IX) and its factor IX clotting antigen (IX:Ag) 500-600 U/mg. Essentially quantitative coupling of the factor IX preparation to activated CH-Sepharose 4B was obtained (4 mg factor IX/ml gel; 2300-3000 U/IX:Ag/ml). This resin bound 1500-2000 U factor IX inhibitor/ml gel and could be re-used at least 5 times without any loss in binding capacity. The binding capacity was dependent on the flow rate. No signs of activation of the coagulation, fibrinolytic, or complement system were observed in vitro. Using this factor IX resin, factor IX alloantibodies were isolated and found to consist of two portions, one minor bound to the resin only in the presence of Ca2+ and another major portion Ca2+ independent. The specific inhibitory activity/milligram IgG of the Ca2+-dependent alloantibodies was about 5 times higher in the presence of Ca2+. It is concluded that 25 ml of the factor IX resin described can remove about 40,000 factor IX inhibitor units (comparable to 120,000 Bethesda U) in one run, provided the flow rate does not exceed 20 ml/hr. By using such a technique for removal of antibodies it seems feasible to convert hemophilia-B patients complicated with inhibitors against factor IX into ordinary hemophilia- B patients for treatment at an emergency or in association with major surgery.     

Postprandial Nutrient Handling and Gastrointestinal Hormone Secretion After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy

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Knowledge of disease and adherence in adult patients with haemophilia

Summary. Patients with moderate and severe haemophilia are evaluated on a regular basis at their haemophilia centres but patients with mild haemophilia are seen less often because of fewer problems related to their disease. The needs of patients with milder forms of haemophilia, however, are often underestimated, both by the patient and staff at healthcare facilities. This study evaluated the knowledge of disease and adherence to treatment among patients with severe, moderate and mild haemophilia. This was a prospective multicentre study performed in Haemophilia Centres in Scandinavia. A total of 413 (67%) of 612 patients aged >25 years with mild, moderate and severe haemophilia completed a self‐administered questionnaire. The mean age of the respondents was 49.7 years (range 25–87 years). Of the 413 respondents, 150 had a mild, 86 had a moderate and 177 had a severe form of haemophilia. A total of 22 (5%) patients did not know the severity of their disease, and 230 (56%) patients knew the effect of factor concentrate in the blood. Of the 413 respondents, 53 (13%) of the cohort never treated a haemorrhage. Patients with mild haemophilia, P ≤ 0.001, were the least likely to treat a haemorrhage. The relative number of patients who were afraid of virus transmission by factor concentrate was about similar in the three groups, 27% of those with severe haemophilia, 26% with moderate and 24% with mild haemophilia. This study shows that the amount of knowledge among haemophilia patients about their disease and treatment is somewhat limited, and demonstrates the importance of continually providing information about haemophilia and treatment, especially to patients with a mild form of the disease.     

Addition of interferon-alpha to a standard maturation cocktail induces CD38 up-regulation and increases dendritic cell function

Monocyte-derived dendritic cells (DCs) are used as adjuvant cells in cancer immunotherapy and have shown promising results. In order to obtain full functional capacity, these DCs need to be maturated, and the current “gold standard” for this process is maturation with TNF-α, IL-1β, IL-6 and PGE₂ used for generating standard DCs (sDC). Several studies indicate that IFN-α might also be important for DC differentiation and maturation. In this study, we tested the effect of IFN-α alone or as addition to the gold standard sDC cocktail. We observed that maturation by IFN-α differs from sDC maturation: The major phenotypic change after IFN-α maturation was dose-dependent up-regulation of CD38 but not CD83, while sDCs expressed the opposite profile with low CD38 and high CD83 expression. Similarly, maturation by Poly I:C leads to CD38high, CD83low DCs indicating a functional relationship between CD38, IFN-α and TLR3. Thus, CD38 appear to be a relevant marker for activation by TLR3 or IFN-α. Addition of IFN-α to the sDC cocktail results in up-regulation of both CD38 and CD83 and improved capacity for induction of autologous T-cell responses despite few other changes in DC phenotype and cytokine secretion. Our observations suggest that IFN-α could be included in maturation protocols for clinical grade DCs used for immunotherapy against cancer and should be included if DCs are used for CD8+ T-cell stimulation in vitro.     

Characterization of monocyte-derived dendritic cells maturated with IFN-alpha

Dendritic cells (DC) are promising candidates for cancer immunotherapy. These cells can be generated from peripheral blood monocytes cultured with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). In order to obtain full functional capacity, maturation is required, but the most potent reagents such as LPS or polyriboinosinic polyribocytidylic acid (Poly I:C) are not approved for clinical use. We tested the ability of type I interferon (IFN) to induce such maturation. We found that 24-h IFN-alpha co-culture of day 7 monocyte-derived DC generated with GM-CSF and IL-4 induces increased numbers of DC positive for CD54 and CD40 together with the co-stimulatory molecule CD80 but not the activation marker CD83. Also, IFN-alpha maturation leads to an increase in IP-10 and MCP-1 chemokine secretion, but only a minor increase in IL-12p40 secretion. In line with this, maturation with IFN-alpha has only a small effect on induction of autologous T-cell stimulatory capacity of the DC. However, an increase in DC allogeneic T-cell stimulatory capacity was observed. These data suggest that IFN-alpha has a potential as a maturation agent used in DC-based cancer vaccine trials, but not as a single reagent.     

Dissection of T-cell antigen specificity in human melanoma

Tumor-infiltrating lymphocytes (TIL) isolated from melanoma patients and expanded in vitro by interleukin (IL)-2 treatment can elicit therapeutic response after adoptive transfer, but the antigen specificities of the T cells transferred have not been determined. By compiling all known melanoma-associated antigens and applying a novel technology for high-throughput analysis of T-cell responses, we dissected the composition of melanoma-restricted T-cell responses in 63 TIL cultures. T-cell reactivity screens against 175 melanoma-associated epitopes detected 90 responses against 18 different epitopes predominantly from differentiation and cancer-testis antigens. Notably, the majority of these responses were of low frequency and tumor-specific T-cell frequencies decreased during rapid expansion. A further notable observation was a large variation in the T-cell specificities detected in cultures established from different fragments of resected melanoma lesions. In summary, our findings provide an initial definition of T-cell populations contributing to tumor recognition in TILs although the specificity of many tumor-reactive TILs remains undefined.