Huge left atrial thrombus and valve degeneration in a patient with a bioprosthetic, porcine, mitral valve

A 43 year old man with a Hancock porcine bioprosthetic valve in the mitral position developed a huge thrombus filling the entire left atrium and chronic degeneration of the bioprosthetic mitral valve. The effective valve orifice was less than 2 mm. These severe findings leading to the patient's death remained undetected while he was alive. This case illustrates the great need for a serial phonoechocardiographic studies in all patients with prosthetic valves.     

Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea- and placebo-receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of $12,160 (95% CI: $9,440, $14,880) for hydroxyurea and $17,290 (95% CI: $13,010, $21,570) for placebo. The difference in means was $5,130 (95% CI: $60, $10,200; P = 0.048). Chest syndrome was the next largest cost with a mean difference of $830 (95% CI: $-340, $2,000; P = 0.16). The hydroxyurea arm was also associated with lower costs for emergency department visits, transfusion, and use of opiate analgesics. In total, the annual average cost per patient receiving hydroxyurea was $16,810 (95% CI: $13,350, $20,270) and the annual average costs per patient receiving placebo was $22,020 (95% CI: $17,340, $26,710). The difference in means was $5,210 (95% CI: $-610, $11,030; P = 0.21). The cost of hydroxyurea with the more intensive monitoring required when using this drug appears to be more than offset by decreased costs for medical care of painful crisis and analgesic use. Although the total cost difference was not significant statistically, these results suggest that hydroxyurea therapy is cost-effective compared to placebo in the management of adult patients with sickle cell anemia. If hydroxyurea can prevent development of chronic organ damage, long-term savings may be even greater.     

The vaso-occlusive pain crisis in sickle cell disease: Definition,pathophysiology, and management

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.     

NK cytokine secretion and cytotoxicity occur independently of the SLP-76 adaptor protein.

The adapter protein SLP-76 is required for T cell development and TCR signal transduction. SLP-76 is also expressed in NK cells, yet splenic populations of NK cells develop normally in SLP-76-deficient mice. We examined the effects of SLP-76 deficiency upon cellular activation through studies of NK function in SLP-76(-/-) mice. This study presents evidence that NK populations in both spleen and liver of SLP-76(-/-) mice remain intact. Natural cytotoxic responses of SLP-76(-/-) splenocytes proceed in a manner comparable to those of wild-type control splenocytes. Similar to controls, SLP-76(-/-) splenocytes exhibit enhanced survival and augmented cytotoxic capacity after in vitro culture with IL-2. IL-2-stimulated SLP-76(-/-) splenocytes also retain normal antibody-dependent cellular cytotoxicity and the ability to secrete IFN-gamma in response to IL-12 stimulation. These results indicate that, unlike events stimulated by TCR engagement, signaling cascades engaged by IL-2 and IL-12 receptors, by Fc gammaRIIIA (which mediates antibody-dependent cellular cytotoxicity), and by natural cytotoxicity-associated receptors on murine NK cells can occur independently of SLP-76.     

Population sub-structuring among <Emphasis Type="Italic">Trypanosoma evansi</Emphasis> stocks

To investigate the population genetic structure of Trypanosoma evansi from domesticated animals, we have analysed 112 stocks from camels, buffaloes, cattle and horses using the tandemly repeated coding sequence (MORF2) and minisatellite markers 292 and cysteine-rich acidic integral membrane protein (CRAM). We recorded a total of six alleles at the MORF2 locus, seven at 292 and 12 at the CRAM loci. Nei’s genetic distance showed reduced allelic diversity between buffaloes and cattle stocks (1.2) as compared to the diversity between camels and buffaloes (3.75) and camels and cattle stock (1.69). The mean index of association (I _A = 0.92) significantly deviated from zero, and the average number of multilocus genotypes (G/N ratio) was 0.21. Twenty-four multilocus genotypes were defined from the combination of alleles at the three loci. The Kenyan sub-populations showed F _st = 0.28 and analysis of molecular variance showed significant divergence (22.7%) between the Laikipia, Kulal and Galana regions. The regional and host distribution of multi-locus genotypes significant population differentiation and high Nei’s genetic distances suggest existence of genetic sub-structuring within T. evansi stocks while the few multi-locus genotypes and deviation of association index from zero indicate the lack of recombination. In conclusion, this study reveals that some genetic sub-structuring does occur within T. evansi, which has a clonal population structure.     

Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis

BACKGROUND: Rush immunotherapy (RIT) presents an attractive alternative to standard immunotherapy. However, RIT carries a much greater risk of acute allergic reactions, including anaphylaxis. OBJECTIVES: We hypothesized that omalizumab, a humanized monoclonal anti-IgE antibody, would be effective in enhancing both safety and efficacy of RIT. METHODS: Adult patients with ragweed allergic rhinitis were enrolled in a 3-center, 4-arm, double-blind, parallel-group, placebo-controlled trial. Patients received either 9 weeks of omalizumab (0.016 mg/kg/IgE [IU/mL]/mo) or placebo, followed by 1-day rush (maximal dose 1.2-4.0 mug Amb a 1) or placebo immunotherapy, then 12 weeks of omalizumab or placebo plus immunotherapy. RESULTS: Of the 159 patients enrolled, 123 completed all treatments. Ragweed-specific IgG levels increased >11-fold in immunotherapy patients, and free IgE levels declined >10-fold in omalizumab patients. Patients receiving omalizumab plus immunotherapy had fewer adverse events than those receiving immunotherapy alone. Post hoc analysis of groups receiving immunotherapy demonstrated that addition of omalizumab resulted in a 5-fold decrease in risk of anaphylaxis caused by RIT (odds ratio, 0.17; P = .026). On an intent-to-treat basis, patients receiving both omalizumab and immunotherapy showed a significant improvement in severity scores during the ragweed season compared with those receiving immunotherapy alone (0.69 vs 0.86; P = .044). CONCLUSION: Omalizumab pretreatment enhances the safety of RIT for ragweed allergic rhinitis. Furthermore, combined therapy with omalizumab and allergen immunotherapy may be an effective strategy to permit more rapid and higher doses of allergen immunotherapy to be given more safely and with greater efficacy to patients with allergic diseases.     

Sequential nitric oxide measurements during the emergency department treatment of acute vasoocclusive sickle cell crisis

This prospective study was designed to examine the relationship between serial serum nitric oxide (NO) levels and pain during the emergency department (ED) treatment of acute vasoocclusive sickle cell crisis (SCC). 102 patient visits, age > or =18 years of age, presenting to the ED with uncomplicated, typical SCC pain had serum NO levels obtained at 2-hr intervals during treatment of pain and were measured using an NO-specific chemiluminesence technique. Pain was measured prior to each NO measurement using a 10 cm visual analog scale (VAS), and subjects were divided into a persistent pain group and an improved pain group. Patients with persistent pain had significantly low initial NO levels (11.51 microM +/- 2.8, P < 0.05) while those with pain improvement had higher initial NO levels (18.1 microM +/- 3.08, P < 0.05). There was no significant correlation between changes in NO and changes in pain scores. These results suggest that the initial NO level may serve as a marker for the severity of tissue ischemia. Sequential NO levels do not appear useful in predicting the course of SCC.