Immune Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria

Somatic mutation in the PIG-A gene is the initial event in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), but the pathophysiologic mechanisms leading to clonal expansion remain unclear. The intricate association of PNH with immune-mediated bone marrow failure syndromes, including aplastic anemia (AA), suggests an immunologic selection process for the glycosylphosphatidyl-inositol (GPI)-deficient hematopoietic clone. The mechanism for the growth advantage of PNH cells may be related to the nature of the antigens targeted by the immune response or to the function of immunomodulatory GPI-anchored proteins on the surface of the hematopoietic target cells. Alternative theories of PNH evolution may include intrinsic properties of the mutated cells, but the experimental evidence is largely lacking. Elucidation of the pathogenesis of PNH may provide key information about the causes of idiopathic AA and help understand the regulation of the hematopoietic stem cell compartment.     

Mycotic aneurysm of the abdominal aorta in a patient undergoing hemodialysis: an unusual complication of Staphylococcus aureus bacteremia.

When Staphylococcus aureus is repeatedly positive in blood cultures even under effective antibiotics therapy (vancomycin, teicoplanin, or rifampin), computed tomography scan and sonography should be performed early to exclude mycotic aneurysm of the deeply seated arteries, especially in patients with abdominal aortic calcification. Before 1990, the most common causative organism of suprarenal aortic mycotic aneurysm was Salmonella; since 1990, it has been gram-positive cocci (i.e., Streptococcus and Staphylococcus) rather than gram-negative bacilli (i.e., Salmonella), possibly because of the more invasive procedures performed in clinical settings, but this hypothesis needs further investigation.     

High-resolution genomic arrays facilitate detection of novel cryptic chromosomal lesions in myelodysplastic syndromes

OBJECTIVE: Unbalanced chromosomal aberrations are common in myelodysplastic syndromes and have prognostic implications. An increased frequency of cytogenetic changes may reflect an inherent chromosomal instability due to failure of DNA repair. Therefore, it is likely that chromosomal defects in myelodysplastic syndromes may be more frequent than predicted by metaphase cytogenetics and new cryptic lesions may be revealed by precise analysis methods. METHODS: We used a novel high-resolution karyotyping technique, array-based comparative genomic hybridization, to investigate the frequency of cryptic chromosomal lesions in a cohort of 38 well-characterized myelodysplastic syndromes patients; results were confirmed by microsatellite quantitative PCR or single nucleotide polymorphism analysis. RESULTS: As compared to metaphase karyotyping, chromosomal abnormalities detected by array-based analysis were encountered more frequently and in a higher proportion of patients. For example, chromosomal defects were found in patients with a normal karyotype by traditional cytogenetics. In addition to verifying common abnormalities, previously cryptic defects were found in new regions of the genome. Cryptic changes often overlapped chromosomes and regions frequently identified as abnormal by metaphase cytogenetics. CONCLUSION: The results underscore the instability of the myelodysplastic syndromes genome and highlight the utility of array-based karyotyping to study cryptic chromosomal changes which may provide new diagnostic information.     

Palliative MEFLEP therapy in advanced pancreatic cancer: excellent response in a patient with Her-2/neu amplification

INTRODUCTION: Patients with pancreatic cancer often present initially in advanced disease with many compromising factors, and yet they may still be responsive to chemotherapy. AIMS: The response of 23 patients with advanced pancreatic cancer to continuous infusion therapy was investigated. METHODOLOGY: From September 1995 to February 1998, 23 patients with advanced pancreatic cancer, many with compromising factors, were treated with a MEFLEP regimen: biweekly 24-hour infusions of etoposide, 5-fluorouracil, leucovorin, epirubicin, and cisplatin, all given through an infusion pump, plus megestrol acetate, 160 mg/d, taken daily. A total of 145 courses were given. Overall response rate was 21% (4/19) for assessable chemo-naive patients; median survival for all 23 patients was 6 months; 22% of patients were alive at 1 year; and a clinical response benefit was attained in 35%. RESULTS: Toxicity was manageable; grade 3 or 4 leukopenia occurred in 1 patient each, 1 patient had fever and grade 3 infection, and grade 3 and 4 hyperammonemic encephalopathy developed in 3 and 1 patients, respectively. All four of the latter patients recovered uneventfully within 2 days of initiation of therapy. Nine patients were evaluated by fluorescence in situ hybridization for the Her-2/neu oncogene, but for only one patient did amplification of the gene occur. She attained complete remission with treatment and lived for 26.7 months after diagnosis. CONCLUSION: Biweekly MEFLEP is an active and manageable regimen for patients with advanced pancreatic cancer with compromised clinical status.     

Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte,Philippines: II. Cellular immune responses to S. japonicum recombinant and native antigens

Cellular immune responses to specific Schistosoma japonicum recombinant and native antigens were investigated in a defined study population of 155 individuals in the Philippines, where data collected from a 3-year observation of exposure, infection and reinfection pattern were used to categorically classify putative 'resistant' and 'susceptible' individuals. Using peripheral blood mononuclear cells (PBMC) of individuals enrolled in the study, in vitro lymphocyte proliferation and cytokine (IFN-gamma, IL-5 and IL-10) production in response to defined recombinant antigens (97 kDa paramyosin, 22 kDa tegumental antigen, 37 kDa glyceraldehyde-3-phosphate dehydrogenase, 14 kDa fatty acid binding protein and 28 kDa gluthathione-S-tranferase) and native antigen soluble worm antigen preparation (SWAP) were measured. Cellular responses to the recombinant and SWAP antigens suggest that Th1 type of response appear to be important in predicting resistance in this population. Of the five recombinant antigens tested, rPMY induced significant levels of IFN-gamma. The production of IL-10, a Th2-type cytokine was strongly implicated in immune regulation. Of importance was the evidence found for SWAP and rPMY induced IFN-gamma responses in predicting 'resistance'. It was noted that these associations were significant even after the effect of age and sex were accounted for in a multivariate analysis.     

Evaluation of ocular arterial changes in glaucoma with color Doppler ultrasonography.

The purpose of this study was to evaluate hemodynamic changes of the retrobulbar vasculature caused by different intraocular pressures with color Doppler ultrasonography. Fifty normal eyes in 25 patients, 13 patients with normal tension glaucoma, and 19 patients with acute glaucoma and increased intraocular pressure (greater than 30 mm Hg) were enrolled in this study. In 15 of 19 patients with acute glaucoma patients, follow-up color Doppler ultrasonography was also undertaken after laser peripheral iridectomy when the intraocular pressure had returned to normal. The peak systolic velocity, end diastolic velocity, resistive index, time average maximum velocity, and pulsatility index were compared in different vessels, including the central retinal artery, lateral posterior ciliary artery, medial posterior ciliary artery, and ophthalmic artery in each orbit. The peak systolic velocity, end diastolic velocity, and time average maximum velocity of the central retinal artery were significantly lower (P<0.01) in acute glaucoma patients than in the control group. The resistive index and pulsatility index of the central retinal artery were significantly higher (P<0.01) in acute glaucoma patients than in the control group. The end diastolic velocity of the lateral and medial posterior ciliary arteries was significantly lower in patients with acute glaucoma than in the control group, and the resistive index and pulsatility index of both of these arteries were significantly higher (P<0.001) in patients with acute glaucoma than in the control group. However, no statistical significantly differences were found in the peak systolic velocity or time average maximum velocity in either of the posterior ciliary arteries; similarly, no statistically significant differences were noted in any of the parameters in the ophthalmic artery between the control group and the group with acute glaucoma. The pulsatility index of the central retinal artery and of the lateral and medial posterior ciliary arteries was significantly lower (P<0.01) in acute glaucoma patients after laser therapy than in acute glaucoma patients before laser therapy. The resistive index of both posterior ciliary arteries was also significantly lower (P<0.004) in acute glaucoma patients after laser therapy than before laser therapy. All parameters for all vessels examined among the normal subjects, the patients with normal tension glaucoma, and the patients with acute glaucoma after laser therapy when the intraocular pressure had returned to normal showed no statistically significant differences. Color Doppler ultrasonography is a good modality for both imaging and studying the hemodynamics of the perioptic nerve vessels.