Citations

Abstract Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma. It has an overall incidence of 2.5/million/year. The median age at diagnosis is 63 years. The clinical manifestations are hepatomegaly (20%), splenomegaly (15%), and lymphadenopathy (15%). The most common symptom is fatigue related to a normochromic, normocytic anemia, and the median hemoglobin value at diagnosis is 10 gm/dl. All patients with Waldenström's macroglobulinemia have a circulating tumor marker, the monoclonal IgM protein. Occasionally high levels of the IgM monoclonal protein can produce a hyperviscosity syndrome manifested by oronasal bleeding. Occasionally retinal hemorrhage or serious neurologic complications, such as somnolence or coma, may occur. The most important prognostic factors are hemoglobin, age, weight loss, and a cryoglobulin. Therapy has included alkylating agents, particularly chlorambucil, purine nucleoside analogs such as fludarabine or cladribine, and most recently the use of rituximab. The median survival of symptomatic patients is 65 months. Patients without symptoms should not be treated.

Abstract Objectives To characterize the presentation and outcome of patients with heart failure (HF) after myocardial infarction (MI) according to left ventricular ejection fraction (LVEF) and test the hypothesis that the outcome of HF did not change over time. Background Little is known about the presentation and outcome of HF post-MI and how these may have changed over time. Methods Using the Rochester Epidemiology Project, all residents of Olmsted County, Minnesota who experienced an incident MI between 1979 and 1998 were identified; MI and HF were validated using standardized criteria. Subjects were followed through their community medical record. Results Between 1979 and 1998, 1915 patients with incident MI and no prior history of HF were identified. Of these, 791(41%) experienced new onset HF as defined by Framingham criteria during 6.6±5.0 years of follow-up. Forty-seven percent were men, mean age was 73±12 years. Forty-four percent had impaired LVEF, 18% preserved LVEF and 38% had no LVEF measurement within 60 days after the HF event. Median survival after HF onset was 4 years and at 5 years after HF onset, only 45% were alive. Older age, male sex, comorbidity, hypertension and no LVEF assessment were associated with increased risk of death, however, patients with impaired LVEF had the worst outcome. Over time, survival did not improve (HR for year: 1.00; 95% CI 0.99, 1.02; P=0.919) even after adjustment for baseline characteristics. Conclusion In this geographically defined cohort of patients with MI, new onset HF after the MI was frequent. When measured, LVEF was most frequently reduced, consistent with systolic heart failure. Mortality was high and did not decline over time and death was independently associated with male sex, older age, hypertension and comorbidity. It also differed according to LVEF, which was inconsistently ascertained in this setting, potentially representing practice opportunities.

Fluorescence techniques for monitoring single-molecule dynamics in the vertical dimension currently do not exist. Here we use an atomic force microscope to calibrate the distance-dependent intensity decay of an evanescent wave. The measured evanescent wave transfer function was then used to convert the vertical motions of a fluorescent particle into displacement (SD = <1 nm). We demonstrate the use of the calibrated evanescent wave to resolve the 20.1 ± 0.5-nm step increases in the length of the small protein ubiquitin during forced unfolding. The experiments that we report here make an important contribution to fluorescence microscopy by demonstrating the unambiguous optical tracking of a single molecule with a resolution comparable to that of an atomic force microscope.

SUMMARYMurine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves’ hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

Objective— Endothelial progenitor cells (EPCs) display a unique aptitude to promote angiogenesis and restore endothelial function of injured vessels. How progenitor cells can execute a regenerative program in the unfavorable environment of injury/inflammation-induced oxidative stress is poorly understood. We hypothesized that EPCs are resistant to oxidative stress and that this resistance is due to high expression and activity of antioxidant enzymes. Methods and Results— EPCs outgrown from human blood of healthy subjects demonstrated a marked resistance to cytotoxic effect of LY83583 (an generator), tumor necrosis factor-α, and serum depletion. LY83583 inhibited in vitro tube formation by human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (CAECs), but not by EPCs. Compared with HUVECs and CAECs, EPCs exhibited ≈3- to 4-fold higher expression and activity of manganese superoxide dismutase (MnSOD), but not copper zinc superoxide dismutase (CuZnSOD) or catalase. The antioxidant profile in EPCs was associated with preservation of the mitochondrial network when exposed to LY83583. Moreover, cytotoxic effects of LY83583 on CAECs and HUVECs were reversed by adenoviral overexpression of MnSOD. Conclusions— Human EPCs are resistant to oxidative stress. High intrinsic expression of MnSOD is a critical mechanism protecting EPCs against oxidative stress.

AbstractPrevious studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3′-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.

ABSTRACT The human monoclonal antibody rHIgM22 enhances remyelination following spinal cord demyelination in a virus‐induced murine model of multiple sclerosis. Using three‐dimensional T2‐weighted in vivo spinal cord magnetic resonance imaging (MRI), we have therefore assessed the extent of spinal cord demyelination, before and after 5 weeks of treatment with rHIgM22, to determine whether antibody enhanced remyelination can be detected by MRI. A significant decrease was seen in T2 high signal lesion volume following antibody treatment. Histologic examination of the spinal cord tissue reveals that this decrease in lesion volume correlates with antibody promoted remyelination. To show that rHIgM22 enters the spinal cord and colocalizes with demyelinating lesions, we used ultrasmall superparamagnetic iron oxide particle (USPIO)‐labeled antibodies. This may be considered as additional evidence to the hypothesis that rHIgM22 promotes remyelination by local effects in the lesions, likely by binding to CNS cells. The reduction in high signal T2‐weighted lesion volume may be an important outcome measure in future clinical trials in humans.

Abstract OBJECTIVE To evaluate tumor control rates and complications after stereotactic radiosurgery for patients with nonfunctioning pituitary adenomas. METHODS Between 1992 and 2000, 33 patients underwent radiosurgery for treatment of nonfunctioning pituitary adenomas. Thirty-two patients (97%) had undergone one or more previous tumor resections. Twenty-two patients (67%) had enlarging tumors before radiosurgery. The median tumor margin dose was 16 Gy (range, 12–20 Gy). The median follow-up period after radiosurgery was 43 months (range, 16–106 mo). RESULTS Tumor size decreased for 16 patients, remained unchanged for 16 patients, and increased for 1 patient. The actuarial tumor growth control rates at 2 and 5 years after radiosurgery were 97%. No patient demonstrated any decline in visual function. Five of 18 patients (28%) with anterior pituitary function before radiosurgery developed new deficits, at a median of 24 months after radiosurgery. The actuarial risks of developing new anterior pituitary deficits were 18 and 41% at 2 and 5 years, respectively. No patient developed diabetes insipidus. CONCLUSION Stereotactic radiosurgery safely provides a high tumor control rate for patients with recurrent or residual nonfunctioning pituitary adenomas. However, despite encouraging early results, more long-term information is needed to determine whether radiosurgery is associated with lower risks of new endocrine deficits and radiation-induced neoplasms, compared with fractionated radiotherapy.