Citations

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.)

Background Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer's disease (AD) in postmenopausal women and may have value in primary prevention. Purpose A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial. Methods The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing. Results Enrollment began in March 1998. In response to the Women's Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants' mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment. Limitations Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed. Clinical Trials 2008; 5: 523—533. http://ctj.sagepub.com

WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although WAVE2 mediates integrin affinity maturation by recruiting vinculin and talin to the immunological synapse in an Arp2/3-dependent manner, the mechanism by which it regulates integrin clustering is unclear. We show that the Abl tyrosine kinase associates with the WAVE2 complex and TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we show that WAVE2 regulates TCR-mediated activation of the integrin regulatory guanosine triphosphatase Rap1 via the recruitment and activation of the CrkL–C3G exchange complex. Moreover, we demonstrate that although Abl does not regulate the recruitment of CrkL–C3G into the membrane, it does affect the tyrosine phosphorylation of C3G, which is required for its guanine nucleotide exchange factor activity toward Rap1. This signaling node regulates not only TCR-stimulated integrin clustering but also affinity maturation. These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation.

Object The object of this study was to assess the results of unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for management of advanced Parkinson disease (PD). Methods A clinical series of 24 patients (mean age 71 years, range 56–80 years) with medically intractable PD, who were undergoing unilateral magnetic resonance imaging–targeted, electrophysiologically guided STN DBS, completed a battery of qualitative and quantitative outcome measures preoperatively (baseline) and postoperatively, using a modified Core Assessment Program for Intracerebral Transplantations protocol. The mean follow-up period was 9 months. Statistically significant improvement was observed in the Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (18%), the total UPDRS PART III score (31%), the contralateral UPDRS Part III score (63%), and scores for axial motor features (19%), contralateral tremor (88%), rigidity (60%), bradykinesia (54%), and dyskinesia (69%), as well as the Parkinson's Disease Quality of Life questionnaire score (15%) in the on-stimulation state compared with baseline. Ipsilateral symptoms improved by approximately 15% or less. Performance on the Purdue pegboard test improved in the contralateral hand in the on-stimulation state compared with the off-stimulation state (38%, p < 0.05). The daily levodopa-equivalent dose was reduced by 21% (p = 0.018). Neuropsychological tests revealed an improvement in mental flexibility and a trend toward reduced letter fluency. There were no permanent surgical complications. Of the 16 participants with symmetrical disease, five required implantation of the DBS unit on the second side. Conclusions Unilateral STN DBS is an effective and safe treatment for selected patients with advanced PD. Unilateral STN DBS provides improvement of contralateral motor symptoms of PD as well as quality of life, reduces requirements for medication, and possibly enhances mental flexibility. This method of surgical treatment may be associated with a reduced risk and may provide an alternative to bilateral STN DBS for PD, especially in older patients or patients with asymmetry of parkinsonism.

The objective of this study was to assess growth patterns of hyperlipidemic children enrolled in a preventive cardiovascular health clinic. A retrospective chart review of hyperlipidemic children enrolled in the Mayo Clinic Cardiovascular Health Clinic for the Young was performed. All participants were counseled to eat an American Heart Association Step-One Diet and exercise regularly. Weight and height were measured every 3 months. Growth was assessed using attained heights and weights and body-mass index Z scores compared to standard distributions for North American children. Sixty-three patients (33 males and 30 females) were enrolled in the study. Mean age at clinic entrance was 7.8 ± 3.5 years (range: 2 to 16 years). We conclude that participation in a preventive health clinic is generally safe for hyperlipidemic children. However, medical management of hyperlipidemic children must include meticulous surveillance to detect the infrequent occurrence of excessive weight loss or weight stabilization resulting from inappropriate response to dietary counseling.

To study the effect of severe undernutrition on linear growth during adolescence, a report was obtained on the ultimate adult height of 71 patients who had had anorexia nervosa at or before age 16 years. At time of diagnosis (ages 9-16 years) median height percentile was 49; at adult follow-up (ages 18-29 years) the median height percentile was 55. This change favoring growth was statistically significant (p < 0.01). Height percentile was maintained or increased in 45 patients and decreased in 26 patients. In only four patients did it change by more than 20 percentile points downward; in 12 patients height percentile increased by more than 20 points. We conclude that, despite weight loss of up to 45 percent at or before age 16 years, most patients with anorexia nervosa continue to grow in stature according to expected norms.

We report three cases of solitary fibrous tumor (SFT) arising in the orbit. All patients presented with nontender swelling of the affected eye, and one patient presented with nasolacrimal duct obstruction. All three patients had well-circumscribed tumors that had histologic features identical to those of SFT of the pleura (fibrous mesothelioma). The neoplastic cells were purely fibrogenic. They were reactive with antivimentin and CD-34 and demonstrated no smooth muscle or neural differentiation (nonreactive with antibodies to actin, desmin, and S 100 protein). KP-1 (CD-68) immunoreactivity was present focally within the neoplastic cells in all three tumors; however, it was strongly positive within tumor infiltrating macrophages. Electron microscopy per formed on one tumor showed fine fibroblastic differentiation with phagocytic activity confined to infiltrating macrophages. SFT of the orbit is a distinct pathologic entity that merits distinction within the broad group of orbital fibrous tumors. Int J Surg Pathol 2(3):193-198, 1995

Background Complete biceps tendon avulsions are frequently missed on clinical examination, suggesting the need for a reliable diagnostic test. Hypothesis Complete distal biceps avulsions can be reliably detected with the Hook test. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods The hook test was performed by a single surgeon in a cohort of 45 patients undergoing surgical exploration of the distal biceps tendon. While the patient actively supinates with the elbow flexed 90°, an intact hook test permits the examiner to hook his or her index finger under the intact biceps tendon from the lateral side. With an abnormal hook test, indicating distal avulsion, there is no cord-like structure under which the examiner may hook a finger. Results Thirty-three patients had an avulsion and 12 had a partial tear. The hook test was abnormal in 33 of 33 (100%) patients with complete biceps avulsions, and intact in 12 of 12 with partial detachments. However, it was painful in 9 of those 12. In the noninjured contralateral arms, which served as the normal control group, 45 of 45 (100%) had a normal hook test. Magnetic resonance imaging (MRI) diagnosed a complete tear in 11 of 12 patients with partial tears and in 11 of 13 with complete lesions. The sensitivity and specificity were both higher with the hook test (both 100%) than with MRI (92% and 85%, respectively). Conclusions The hook test is a highly sensitive and specific test for assessment of distal biceps tendon avulsions.

Two interpretations of the Boston Naming Test (BNT) discontinuation rule of "six consecutive failures" were uncovered in an informal survey. The rigorous interpretation includes correct responses to phonemic cues in the count of failures, whereas the lenient interpretation does not. Using both methods to score the same protocols, BNT final scores were changed in 3% of 655 normal elderly persons and in 31% of 140 patients with Alzheimer's Disease (AD). Among normals, discrepant scores were most often found in persons age 80 years and older, and scores differed by up to 16 points. Among AD patients, discrepant scores did not preferentially occur in any age group, but scores differed by up to 10 points. The clinical impact of BNT scoring differences occasionally can be substantial and warrants attention.