Alexis A. Thompson

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

BACKGROUNDnIn patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain.nnnMETHODSnIn a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease.nnnRESULTSnDeath from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin.nnnCONCLUSIONSnPravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation

The association of bone marrow failure and skeletal defects has been frequently noted, but the genetic basis for most of these syndromes remains unclear1. We have identified an unusual association of amegakaryocytic thrombocytopenia and radio-ulnar synostosis in two unrelated and nonconsanguinous families that are of different ethnic backgrounds (Fig. 1a). The fathers and all affected children in both families have the same skeletal defect, proximal fusion of the radius and ulna (Fig. 1b), resulting in extremely limited pronation and supination of the forearm. Three children also had symptomatic thrombocytopenia, with bruising and bleeding problems since birth, necessitating correction by bone marrow or umbilical-cord stem-cell transplantation. The fathers had normal platelet counts and no history of bleeding or bruising. This set of clinical findings appears distinct from any other syndromes of bone marrow failure and skeletal malformations, including thrombocytopenia with absent radii (TAR) syndrome and Fanconi anaemia1, 2, 3. So far, proximal radial-ulnar synostosis has not been associated with the TAR syndrome, which, as its name implies, typically has a more pronounced radial defect. The absence of excessive diepoxybutane-induced chromosomal breakage before stem cell transplantation from our patients is not consistent with Fanconi anaemia.

R2* imaging of transfusional iron burden at 3T and comparison with 1.5T

To determine normative R2* values in the liver and heart at 3T, and establish the relationship between R2* at 3T and 1.5T over a range of tissue iron concentrations.

Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome

The association of bone marrow failure and skeletal defects has been frequently noted, however, the genetic basis for most of these syndromes remains unclear. We describe a previously uncharacterized autosomal dominant syndrome of amegakaryocytic thrombocytopenia associated with radial‐ulnar synostosis. The clinical features of this syndrome appear to be distinct from other similar conditions, including Fanconis anaemia and thrombocytopenia‐absent radii (TAR). The physical findings at diagnosis and clinical management of each case are detailed, as well as a discussion of this disorder in the context of other syndromes in which marrow failure and skeletal defects are prominent features. We also review recent developments in molecular genetics that may provide important clues to the underlying aetiology of this condition.

Intraoperative pediatric blood transfusion therapy: a review of common issues. Part II: transfusion therapy, special considerations, and reduction of allogenic blood transfusions

Massive blood transfusion is defined as the loss of one or more circulating blood volumes. It is, therefore, important to calculate the patient’s estimated blood volume (EBV) and to relate this to the volume of blood products and other fluids administered (Table 1). In addition the anesthesiologist should estimate how much blood will be allowed to be lost before the initiation of packed RBC transfusion. The patient’s EBV is generally related in part to the patient’s age as well as body habitus. Younger patients have a higher fraction of their weight as blood while more obese patients have a lower fraction. Once the patient’s circulating blood volume has been estimated then a further simple calculation allows estimation of the maximal allowable blood loss (MABL). A simple mathematical calculation is:

Tricuspid regurgitant jet velocity is associated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension

Tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec. on echocardiography is a surrogate marker for pulmonary hypertension (PHT) in adults with sickle cell disease (SCD). We prospectively examined the relationship between TRJV and laboratory markers of hemolysis in 51 children and young adults with SCD at baseline. We found significant correlations between TRJV and lactate dehydrogenase (LDH), hemoglobin (Hb), reticulocyte count (retic) and aspartate aminotransferase (AST). LDH, retic and AST were significantly higher and Hb was lower in subjects with TRJV ≥ 2.5 m/sec. We conclude that hemolysis significantly contributes to TRJV elevation in children and young adults with SCD.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short‐ and long‐term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

Intraoperative pediatric blood transfusion therapy: A review of common issues. Part I: Hematologic and physiologic differences from adults; metabolic and infectious risks

Pediatric intraoperative transfusion therapy, particularly the approach to massive blood transfusion (blood loss ≥one blood volume) can be quite complex because of the unique relationship between the patients blood volume and the volume of the individual blood product transfused. This paper is divided into two parts: part 1 presents an overview of the physiologic and hematologic differences between children and adults as well as an overview of the metabolic consequences of blood transfusions, risks of disease transmission, and blood compatibility issues.

Fracture Prevalence and Relationship to Endocrinopathy in Iron Overloaded Patients with Sickle Cell Disease and Thalassemia

Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age> or =12 years and liver iron concentration> or =10 mg/g dry wt or serum ferritin> or =2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin<500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6+/-0.7 years), 203 subjects with TxSCD (44% Male, 24.7+/-0.9 years: Mean+/-SE), and 65 NonTxSCD (50% Male, 22.2+/-1.3 years) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2-4.6; 95%CI), male gender (OR: 2.6; 1.5-4.5), hypothyroidism (OR: 3.3; 1.1-9.8) and age (OR: 1.1; 1.03-1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.

Aberrant expression and localization of the cytoskeleton-binding pp52 (LSP1) protein in hairy cell leukemia

Non-retractable cell surface projections and cytoskeleton-mediated functional defects are distinguishing features of both hairy cell leukemia (HCL) and neutrophil actin dysfunction (NAD). These defects in NAD neutrophils are attributed to moderate over-expression of pp52 (LSP1), the F-actin-binding, leukocyte-specific phosphoprotein. Here we report that pp52 is similarly elevated in HCL patient PBMCs. Established HCL cell lines exhibited characteristic morphological features like those of fresh HCL cells and showed elevated pp52 levels. The excess pp52 in these HCL cell lines was selectively associated with the F-actin-rich cytoskeletal arrays in surface projections. Treatments producing radical changes in HCL cell shape also altered pp52 expression and intracellular distribution. Alpha interferon (IFNalpha, used to treat HCL) reduced pp52 levels, normalized intracellular pp52 distribution and reverted HCL cells to rounded B cell morphology. Phorbol ester stimulation rapidly generated hyper-phosphorylated pp52 isoforms which translocated from the cytoskeleton to the cytosol prior to the further elongation of surface spikes. This indicates a direct role for phosphorylation in controlling pp52 interactions with the cytoskeleton. Overall, these findings strongly suggest that elevated pp52 expression and/or selective cytoskeletal association contributes to the distinctive morphology of HCL cells.