Human neutrophils lose their surface Fc gamma RIII and acquire Annexin V binding sites during apoptosis in vitro

We have previously reported that neutrophilic granulocytes rapidly release part of their Fc gamma RIII from the plasma membrane upon in vitro activation, probably by proteolytic cleavage. In plasma and other body fluids, released or soluble Fc gamma RIII has been found in considerable amounts. In the present study, neutrophils were kept in maintenance culture for 18 to 24 hours. Forty percent of the neutrophils completely lost Fc gamma RIII, and the remainder of the cells showed a 60% decrease in Fc gamma RIII expression on their surface. Released Fc gamma RIII was detected in the culture supernatant. Nevertheless, more than 90% of the cells was viable as judged by hydrolysis of fluorescein diacetate. The presence of interferon gamma, granulocyte colony-stimulating factor, or granulocyte- macrophage colony-stimulating factor, but not interleukin-3 (IL-3), IL- 6, or IL-8, in the culture medium increased the number of cells that still expressed Fc gamma RIII. We found that this loss of Fc gamma RIII was not the result of cell activation but correlated strongly with apoptosis. The Fc gamma RIII-negative subpopulation exhibited typical morphologic changes, such as nuclear condensation and DNA fragmentation. Furthermore, this subpopulation appeared to have acquired the property of binding Annexin V, a calcium-dependent, phospholipid-binding protein with high affinity for phosphatidylserine. The external exposure of this phospholipid by cells has been reported to occur during apoptosis. The property of Annexin V binding was not shared by the nonapoptotic, Fc gamma RIII-positive subpopulation. In this respect, we identified binding of Annexin V as an convenient marker for apoptotic cells. Our results indicate that soluble Fc gamma RIII in body fluids might be derived for a large part from neutrophils undergoing apoptosis in the tissues.     

Predictability of the t(1;19)(q23;p13) from surface antigen phenotype: implications for screening cases of childhood acute lymphoblastic leukemia for molecular analysis: a Pediatric Oncology Group study

The t(1;19)(q23;p13) translocation occurs in approximately 5% of B- precursor acute lymphoblastic leukemias (ALLs) occurring in children. Its presence has been associated with a poor prognosis, which may be overcome with more intensive therapy. Although leukemic cells from cases of t(1;19)-ALL frequently express cytoplasmic mu heavy chains, their complete antigenic profile remains undefined. Among 697 consecutive cases of B-precursor ALL with complete phenotypic studies using a panel of monoclonal antibodies, 22 cases were found to carry the t(1;19). Twenty of 22 cases had an identical, complex phenotype characterized by homogeneous expression of CD19, CD10, and CD9; complete absence of CD34; and at least partial absence of CD20. Overall, this phenotype was seen in only 8.0% (56 of 697) of childhood B-precursor ALL. One of the two remaining t(1;19)-carrying cases conformed to this phenotype, but was lacking data for CD9. The other case differed by virtue of expression of CD34 and was also hyperdiploid with 55 chromosomes. Molecular studies showed E2A-PBX1 abnormalities in all examined cases (12 of 12) with the t(1;19), including the case lacking CD9 data. In contrast, no E2A-PBX1 abnormalities were detected in the sole t(1;19)-ALL with CD34 expression. Seventeen cases with the characteristic phenotype and uninformative cytogenetics were also molecularly analyzed and 5 of 17 (including 4 of 8 with unsatisfactory cytogenetics and 1 of 9 with a normal karyotype) contained E2A gene rearrangements and E2A-PBX1 fusion mRNAs. Our results show that all cases of t(1;19)-ALL with concomitant E2A-PBX1 fusion invariably express a characteristic but uncommon profile of surface antigens. These observations suggest that selective molecular analysis of a small subset of patients (those with uninformative cytogenetics and the characteristic phenotype) can identify a significant number of additional cases of ALL with E2A-PBX1 fusion that might benefit from more intensive therapy.     

Fatal Amiodarone Hepatoxicity

The antiarrhythmic agent amiodarone is associated with numerous adverse effects, but clinically significant liver disease is rare. A patient is described who presented with muscle weakness, hepatomegaly, and ascites following 28 months of amiodarone usage. His condition deteriorated despite discontinuation of amiodarone therapy. A postmortem liver biopsy demonstrated necrosis, fibrosis, hyalin, and phospholipid-laden lysosomal lamellar bodies. Resolution of hepatic dysfunction may not necessarily occur on withdrawal of amiodarone if irreversible damage is already established. We speculate as to the reasons for the reportedly low incidence of overt liver disease, and suggest that hepatic enzyme levels, as well as other indicators of hepatic function, such as the serum albumin concentration, be monitored indefinitely in all patients while taking amiodarone.     

Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis

BACKGROUND & AIMS: Approximately 13% of patients with chronic hepatitis D virus (HDV) infection have liver-kidney microsomal antibodies type 3 (LKM-3) directed against family 1 uridine 5'-diphosphate-glucuronosyl- transferases (UGT-1). The aim of this study was to characterize the prevalence and specificity of LKM-3 by recombinant antigen testing systems. METHODS: Enzyme-linked immunosorbent assay (ELISA) and Western blot were performed using baculovirus-generated human UGT-1.1 and -1.6 and rabbit UGT-1.6. Sera from patients with HDV (n = 50), autoimmune hepatitis (AIH) type 2 (n = 50), hepatitis B virus (n = 26), hepatitis C virus (HCV) (n = 25), and LKM-1 autoantibody-positive HCV (n = 14) and sera from normal controls (n = 50) and italian patients with HDV and known LKM-3 autoantibodies were studied. RESULTS: Six percent of patients with HDV from Germany and 8% of patients with type 2 AIH had LKM-3. Sera from italian patients with HDV and patients with AIH type 2 recognized all three recombinant UGT-1. HDV sera from Germany selectively recognized human UGT-1. LKM-3 titers were lower in HDV than in AIH. One patient with AIH had LKM-3 as the only marker of AIH. CONCLUSIONS: This study indicates a molecular target and titer difference of LKM-3 autoantibodies in German subjects with HDV and AIH. It also suggests a geographic target and titer difference of LKM-3 in HDV. LKM-3 are identified as a rare and previously undescribed independent marker of AIH. (Gastroenterology 1996 Dec;111(6):1576-86)     

Causes and mechanisms of nondipping hypertension

Growing evidence indicates that nondippers have worsened cardiovascular outcomes than dippers. Ambulatory blood pressure monitoring with a lack of nocturnal BP fall (nondipping) have also been shown to be more closely associated with target organ damage and worsened cardiovascular outcome than in patients with essential hypertension with dipping pattern. The underlying pathogenetic mechanisms potentially linking nondipping with cardiovascular disease are not fully understood. There are multiple possible underlying pathophysiologic mechanisms in the impaired BP decline during the night. Extrinsic and intrinsic factors including abnormal neurohormonal regulation, lack of physical activity, nutritional factors such as increased dietary sodium intake, and smoking of tobacco have been implicated for blunted circadian rhythm of BP. Certain diseases such as diabetes and chronic renal diseases also affect the circadian BP rhythm. Currently, the clinical importance of nondipping is known well; however, the relationship between certain disease states and nondipping has not been fully explained yet. This paper will attempt to address to clarify the underlying basis for nondipping and the specific associations with various disease states.     

Differential north to south gastric cancer-duodenal ulcer gradient in China

There are suggestions that duodenal ulcer protects individuals from gastric cancer and that rice is ulcerogenic while wheat is gastro-protective. We aimed to examine the relationship of gastric cancer, duodenal and gastric ulcers in different geographical regions in China and identified dietary risk factors for duodenal ulcer and gastric cancer. The prevalence of peptic ulcer and gastric cancer among symptomatic patients in eight major cities, four each from the north and the south representing all the six defined regions of China were studied. Endoscopy and case records over a 10 year period were reviewed and cases of confirmed duodenal and gastric ulcer and gastric cancer, together with the total number of endoscopies performed per year, were recorded. Rates were expressed as cases/1000 endoscopies. Results were compared to another epidemiological study on diet and mortality in the same regions in China conducted at the same time. Duodenal ulcer rates were 2.4-fold higher in southern China than northern China, whereas gastric cancer rates were 1.6-fold higher in the north than in the south. Correlation studies showed for the first time an inverse linear relationship between the gastric cancer rates and the duodenal ulcer rates (r=-0.8076, P=0.015), as well as the duodenal ulcer: gastric ulcer ratios (r=-0.9133, P=0.002). Gastric ulcer rates were higher in southern China but did not correlate with the gastric cancer rates (r=0.1455, P=0.731). Duodenal ulcer rates were found to be related to daily rice intake (r=0.8554, P=0.029) and inversely related to daily wheat flour intake (r=-0.8472, P=0.033). Gastric cancer rates were not related to any dietary risk factors tested. We concluded there was an inverse relationship between gastric cancer rates and duodenal ulcer rates. Although duodenal ulceration and gastric cancer are both linked to Helicobacter pylori infection, the findings of this study indicate independent additional aetiological factors for the pathogenesis of these conditions. Dietary factors such as rice or wheat intake may play a role.     

Case report: Successful treatment of recurrent chordoma and bilateral pulmonary metastases following an 11-year disease-free period

INTRODUCTION

Chordomas are rare but aggressive tumors due to local recurrence and distant metastases. They originate commonly in the sphenooccipital and sacrococcygeal regions, and metastasize to the lungs, bone, skin, liver, and lymph nodes. They occur more frequently in men and people over the age of 40.

PRESENTATION OF CASE

A 28 year-old female presented with sacrococcygeal chordoma for which she received wide local excision and adjuvant radiation therapy. She enjoyed an unusual disease-free survival for 11 years until a routine surveillance scan of the pelvis identified local recurrence. Further work up revealed bilateral pulmonary metastases. She underwent local excision of the recurrent tumor and video-assisted thoracoscopic (VATS) wedge resection of pulmonary metastases. She also received adjuvant radiation therapy to the recurrent resection bed. Two years later, she remains free of disease and symptoms.

DISCUSSION

Chordomas are commonly insensitive to chemotherapy and radiation, making surgery the most successful therapeutic modality. However, there are few guidelines on the surveillance and treatment of recurrent chordoma. We report success with aggressive surgical resection of recurrence and metastasis as well as adjuvant radiation therapy.

CONCLUSION

The prolonged survival of our patient underscores the importance of (1) aggressive surgical resection of chordoma, whether primary, recurrent, or metastatic, with adjuvant radiation therapy, (2) minimization of surgical seeding of tumor, and (3) diligent cancer surveillance.