Citations

Background— Coronary bypass surgery (CABG) and angioplasty (PTCA) have been compared in several randomized trials, but data about long-term economic and quality-of-life outcomes are limited. Methods and Results— Cost and quality-of-life data were collected prospectively from 934 patients who were randomized in the Bypass Angioplasty Revascularization Investigation (BARI) and followed up for 10 to12 years. CABG had 53% higher costs initially, but the gap closed to <5% during the first 2 years; after 12 years, the mean cumulative cost of CABG patients was $123 000 versus $120 750 for PTCA, yielding a cost-effectiveness ratio of $14 300/life-year added. CABG patients experienced significantly greater improvement in their physical functioning for the first 3 years but not in later follow-up. Recurrent angina substantially reduced all quality-of-life measures throughout follow-up. Cumulative costs were significantly higher among patients with diabetes, heart failure, and comorbid conditions and among women; costs also were increased by angina, by the number of revascularization procedures, and among patients who died. Conclusion— Early differences between CABG and PTCA in costs and quality of life were no longer significant at 10 to 12 years of follow-up. CABG was cost-effective as compared with PTCA for multivessel disease.

Transcutaneous partial pressure of oxygen (TcPO2) predicts wound healing in critical ischemia. However, no studies have controlled for the effect of wounds on TcPO2. In this study, in 24 hip or knee arthroplasty cases without vascular disease, TcPO2 was measured preoperatively at the incision site, contralaterally, and at a reference site on the chest wall. The measurements were repeated at 2 days and 2 months postoperatively and compared. TcPO2, normal preoperatively, decreased at all sites on the second postoperative day (p < 0.001), with a trend toward a greater decrease at the wound (p 1/4 0.09). All wounds healed, and TcPO2 returned to baseline at all sites 2 months postoperatively. In conclusion, acute surgical wounds are associated with a significant and widespread decrease in cutaneous TcPO2 in the setting of normal arterial perfusion. This decrease is likely multifactorial and deserves further investigation.

Abstract Among 2333 consecutive patients with myelofibrosis with myeloid metaplasia (MMM) seen at our institution, 91 fulfilled the World Health Organization (WHO) criteria for leukemic transformation (LT). All episodes of LT were myeloid in origin (acute myeloid leukemia [AML]) with all French-American-British (FAB) subtypes represented except M3; the most frequent subtypes were M7 (25.4%), M0 (22.4%), and M2 (17.9%). Cytogenetic studies during LT were available in 56 patients and revealed a clonal abnormality in 51 (91%): 30 patients had complex karyotype, 2 had core-binding factor gene lesions, and 18 had abnormalities of chromosome 5 or 7. Karyotypic evolution was documented in the majority of the patients in whom serial analysis was possible. In general, LT was fatal in 98% of the cases after a median of 2.6 months (range, 0-24.2 months). Twenty-four patients received AML-like induction chemotherapy that resulted in no complete remission: 41% reverted into chronic-phase disease and the incidence of treatment-related mortality was 33%. The remaining 67 patients received either supportive care alone (48 patients) or low-intensity chemotherapy (19 patients). Overall, survival was similarly poor in all 3 treatment categories. The outcome of LT in MMM with current therapies is dismal and either supportive care alone or appropriate clinical trials should be considered.

AbstractB-cell chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal lymphocytes resistant to apoptosis. We evaluated the ability of the investigational antileukemic agent adaphostin to induce apoptosis in CLL B cells and synergize with fludarabine in vitro. Analysis by annexin V/propidium iodide (PI) staining revealed that the concentration of adaphostin required to induce 50% cell death (IC50) at 24 hours was 4.2 μM (range, 1.10-11.25 μM; median, 4.25 μM; n = 29) for CLL isolates and more than 10 μM for B and T cells from healthy donors. Immunoblots demonstrated adaphostin induced poly(adenosine diphosphate-ribose) polymerase (PARP) cleavage and cleavage of caspase-3 substrates, suggesting that adaphostin induces apoptosis. Adaphostin increased the level of reactive oxygen species (ROS) within CLL B cells, and the antioxidant N-acetylcysteine blocked both adaphostin-induced ROS generation and apoptosis. Adaphostin also caused a decrease in the level of the antiapoptotic protein Bcl-2. When adaphostin was combined with fludarabine (F-ARA-AMP), a synergistic effect on cell death was observed in all 10 CLL samples. These findings not only indicate that adaphostin induces apoptosis selectively in CLL B cells through a mechanism that involves ROS generation but also demonstrate its ability to augment the effects of fludarabine. Further preclinical development of adaphostin as a novel agent for the treatment of CLL appears warranted.

AbstractImmunoglobulin light chain amyloidosis (AL) is characterized by a clonal expansion of plasma cells within the bone marrow. Gene expression analysis was used to identify a unique molecular profile for AL using enriched plasma cells (CD138+) from the bone marrow of 24 patients with AL and 28 patients with multiple myeloma (MM) and 6 healthy controls. Class prediction analysis (PAM) revealed a subset of 12 genes, which included TNFRSF7 (CD27), SDF-1, and PSMA2, that distinguished between these 2 groups with an estimated and observed accuracy of classification of 92%. This model was validated with an independent dataset of 11 patients with AL and 12 patients with MM with 87% accuracy. Differential expression for the most discriminant genes in the 12-gene subset was validated using quantitative real-time polymerase chain reaction and protein expression analysis, which upheld the observations from the micro-array expression data. Functional analyses using a novel network mapping software revealed a number of potentially significant pathways that were dysregulated in patients with AL, with those regulating proliferation, apoptosis, cell signaling, chemotaxis, and migration being substantially represented. This study provides new insight into the molecular profile of clonal plasma cells and its functional relevance in the pathogenesis of light chain amyloidosis.

The immunosuppressive properties of morbilliviruses including measles and canine distemper virus (CDV) are well known, but the host cells supporting infection are poorly characterized. To identify these cells, a recombinant CDV expressing green fluorescent protein was produced by reverse genetics based on a wild-type strain lethal for ferrets. This recombinant virus fully retained virulence and blazed three lymphocyte-based pathways through the immune system of its host: first, it infected rapidly and massively circulating B and T cells; second, it took over and damaged secondary lymphatic organs including spleen, lymph nodes, and gut-associated and mucosal lymphoid tissues; third, it infected most thymocytes. In contrast, replication in epithelial cells was initially not detectable, but substantial before host death. Thus, CDV initially infects lymphocytes and massively replicates therein, thereby causing immunosuppression and preparing systemic invasion and host escape.

Two patients with cerebrospinal fluid (CSF) leak, one at the level of fourth thoracic spine and another with undetermined level of leak, presented with paradoxical postural headaches in that the headaches were present when in a horizontal position and resolved if the patients were upright. One patient improved spontaneously and the other responded to a targeted epidural blood patch. Paradoxical postural headache is yet another headache type that can be associated with CSF leak and CSF volume depletion. Its mechanism is uncertain, but it could be related to congestion and dilatation of cerebral venous sinuses and large veins.

Abstract Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p &lt; 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.

Eosinophils are often dominant inflammatory cells present in the lungs of asthma patients. Nonetheless, the role of these leukocytes remains poorly understood. We have created a transgenic line of mice (PHIL) that are specifically devoid of eosinophils, but otherwise have a full complement of hematopoietically derived cells. Allergen challenge of PHIL mice demonstrated that eosinophils were required for pulmonary mucus accumulation and the airway hyperresponsiveness associated with asthma. The development of an eosinophil-less mouse now permits an unambiguous assessment of a number of human diseases that have been linked to this granulocyte, including allergic diseases, parasite infections, and tumorigenesis.