Citations

Abstract Background: Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. Content: The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion. Discussion: Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Background and Purpose— Size of an unruptured intracranial aneurysm (UIA) may be an important risk factor for rupture. Accordingly, serial noninvasive imaging is commonly used to assess untreated UIA for enlargement. Few data exist regarding the frequency and predictors of enlargement. We obtained this information from a group of patients followed with serial MR angiography (MRA). Methods— We retrospectively identified 165 patients with 191 UIA followed with serial MRA. Fusiform aneurysms, UIA <2 mm, and UIA that were surgically or endovascularly treated before the first MRA were excluded. MRA was performed using 1.5-T and 3-T MRI. Maximal diameter was determined on MRA source images. Multivariate regression analysis was used to determine independent risk factors for growth. Results— Twenty aneurysms (10%) grew over a median follow-up period of 47 months. Frequency of enlargement was 6.9%, 25%, and 83% for aneurysms <8 mm, 8 to 12 mm, and ≥13 mm, respectively ( P <0.001 for trend). Of the variables we evaluated, original aneurysm diameter (OR, 1.28 per mm; 95% CI, 1.07 to 1.58) was the only independent predictor of enlargement. Aneurysms ≥8 mm in diameter were at highest risk for enlargement (OR, 7.25; 95% CI, 1.96 to 27.1). There was a trend toward increased risk of enlargement in patients with multiple aneurysms (OR, 2.50; 95% CI, 0.86 to 7.53). Conclusions— Over a median follow-up period of 47 months, 10% of UIA enlarged. Larger aneurysms had a significantly increased risk of enlargement. The likelihood of enlargement was highest in aneurysms with diameters ≥8 mm. However, a clinically significant proportion of small aneurysms grow, and this growth can be detected by serial MRA.

Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI − clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI − cells because of a second mutation or a conditional growth advantage of GPI − cells in the presence of an immune attack on normal (GPI + ) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH.

Abstract Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.)

Abstract Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant form of EGFR that is expressed in 40% to 50% of gliomas and several other malignancies. Here, we describe the therapeutic effects of silencing EGFRvIII on glioma cell lines in vitro and in vivo. A small interfering RNA molecule against EGFRvIII was introduced into EGFRvIII-expressing glioma cells (U87Δ) by electroporation resulting in complete inhibition of expression of EGFRvIII as early as 48 h post-treatment. During EGFRvIII silencing, a decrease in the proliferation and invasiveness of U87Δ cells was accompanied by an increase in apoptosis (P &lt; 0.05). Notably, EGFRvIII silencing inhibited the signal transduction machinery downstream of EGFRvIII as evidenced by decreases in the activated levels of Ras and extracellular signal-regulated kinase. A lentivirus capable of expressing anti-EGFRvIII short hairpin RNA was also able to achieve progressive silencing of EGFRvIII in U87Δ cells in addition to inhibiting cell proliferation, invasiveness, and colony formation in a significant manner (P &lt; 0.05). Silencing EGFRvIII in U87Δ cultures with this virus reduced the expression of factors involved in epithelial-mesenchymal transition including N-cadherin, β-catenin, Snail, Slug, and paxillin but not E-cadherin. The anti-EGFRvIII lentivirus also affected the cell cycle progression of U87Δ cells with a decrease in G1 and increase in S and G2 fractions. In an in vivo model, tumor growth was completely inhibited in severe combined immunodeficient mice (n = 10) injected s.c. with U87Δ cells treated with the anti-EGFRvIII lentivirus (P = 0.005). We conclude that gene specific silencing of EGFRvIII is a promising strategy for treating cancers that contain this mutated receptor. [Mol Cancer Ther 2008;7(11):3586–97]

Purpose The purpose of this study was to evaluate the results of arthroscopic capsulolabral repair for traumatic anterior shoulder instability and to compare the outcome in patients who have Bankart lesions versus those with anterior labroligamentous periosteal sleeve avulsion (ALPSA) lesions. Methods This study included 99 patients (93 shoulders), 72 male and 17 female, with a mean age of 32 years, who underwent arthroscopic Bankart repair for traumatic, recurrent anterior shoulder instability, by use of suture anchors. In 67 shoulders (72%) a discrete Bankart lesion was repaired, and in 26 shoulders (28%) an ALPSA lesion was repaired. The 2 groups were analyzed with regard to the number of preoperative dislocations and number of postoperative recurrences. Results At a mean follow‐up of 47 months (range, 24 to 98 months), recurrence of instability was documented in 10 shoulders (10.7%). Of the shoulders, 5 had Bankart lesions (7.4%) and 5 had ALPSA lesions (19.2%) ( P = .0501). The mean number of dislocations or subluxations before the index surgery was significantly higher in the ALPSA group (mean, 12.3 [range, 2 to 57]) than in the Bankart group (mean, 4.9 [range, 2 to 24]) ( P < .05). However, there were no significant differences in the number of anchors used, incidence of minor glenoid erosion, or incidence of bony Bankart lesions between the groups ( P > .05 for all). Conclusions Patients with ALPSA lesions present with a higher number of recurrent dislocations than those with discrete Bankart lesions. In addition, the failure rate after arthroscopic capsulolabral repair is higher in the ALPSA group than in the Bankart group. Level of Evidence Level IV, therapeutic case series.