Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population

Dear Sir, We read the recent article by Franklin and Kutteh (2002), concerningthe pregnancy outcomes of recurrent pregnancy loss (RPL) patientswho had normal obstetrical evaluations with the exception ofpositive antiphospholipid antibodies (aPL) findings. In theirreport distinctions were made between two groups of aPL positiveRPL patients with reference to their aPL specificities. Group1 patients had ‘the common’ aPL, anticardiolipin(aCL), or antiphosphatidylserine antibodies (aPS) and/or a lupusanticoagulant (LAC). For comparisons,     

Health expenditure and finance: who gets what?

The methods used in South Africa's first comprehensive review of health finance and expenditure are outlined. Special measures were adopted to make the process acceptable to all concerned during a period of profound political transition. The estimation of indicators of access to public sector resources for districts sorted by per capita income allowed the health care problems of disadvantaged communities to be highlighted.     

LPS-Induced NF-kappaB activation and TNF-alpha release in human monocytes are protein tyrosine kinase dependent and protein kinase C independent

BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is an important mediator of septic shock. Endotoxin (LPS) signal transduction in human monocytes leads to activation of nuclear factor-kappa B (NF-kappaB) and TNF-alpha release. Previous studies have implicated activation of both protein kinase C (PKC) and protein tyrosine kinases (PTK) in LPS-induced NF-kappaB activation and TNF-alpha production. We hypothesized that inhibition of either PKC or PTK would decrease LPS-induced NF-kappaB DNA binding and TNF-alpha release in human monocytes. MATERIALS AND METHODS: Human monocytes were stimulated with PMA (50 ng/ml) alone or LPS (100 ng/ml) with and without a nonspecific serine/threonine protein kinase inhibitor staurosporine (Stauro), a specific pan-PKC inhibitor bisindolylmaleimide (Bis), or an inhibitor of PTK genistein (Gen). TNF-alpha release in culture supernatants was measured by an ELISA. NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay. RESULTS: LPS increased NF-kappaB DNA binding and TNF-alpha release in human monocytes. Nonspecific protein kinase inhibition inhibited NF-kappaB activation and TNF-alpha release, while specific PKC inhibition with Bis had no effect on LPS-induced NF-kappaB DNA binding or TNF-alpha release. PTK inhibition with Gen attenuated both LPS-induced NF-kappaB DNA binding and TNF-alpha production in human monocytes. Direct activation of PKC with PMA induced both NF-kappaB activation and TNF-alpha production by human monocytes. CONCLUSIONS: These results suggest that LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes are independent of PKC activity. Furthermore, our results provide evidence that PTK plays a role in LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes and thus could be a potential therapeutic target in inflammatory states.     

Angiotropic large B-cell lymphoma with clinical features resembling subacute combined degeneration of the cord

Angiotropic large cell lymphoma is a rare neoplastic disorder associated with a high mortality. The hallmark of the disease is lymphoid proliferation confined to the intravascular compartment without local tissue or vessel wall infiltration [1]. This feature is so striking that the disease was originally thought to arise from endothelial tissue and early cases were described as malignant angioendotheliomatosis. However, application of immunohistochemical methods for detection of lymphoid markers such as the CD45 and CD20 cell surface markers has confirmed its lymphoid origin, usually of B-cell lineage [2]. Clinical manifestations of the disease are protean and are due to multifocal medium and small vessel occlusion by tumour cells [3]. Characteristic sites of involvement are skin and central nervous system and although an ante-mortem diagnosis can be made from a biopsy specimen, it is often unsuspected [4]. We present a case of angiotropic large B-cell lymphoma in a 74-year-old man who presented with urinary symptoms and had a neurological picture resembling subacute combined degeneration of the cord.     

Monoclonal antibodies to human melanoma-associated antigens: an amplified enzyme-linked immunosorbent assay for the detection of antigen, antibody, and immune complexes

An amplified, indirect biotin-avidin micro-enzyme-linked immunosorbent assay was developed for the measurement of human melanoma-associated antigens, either free or circulating with associated immunoglobulin in patient sera. Parameters and specificity of detection were assessed using monoclonal antibody to human melanoma-associated antigens. The main advantages of the assay are its flexibility, through the use of indirect detection and a variety of formats, and its sensitivity, with a lower limit of antibody detection at 100 pg/well and a lower limit of soluble antigen detection at 10 pg/well. The assay was applied to cell surface antigen detection with monoclonal antibody 9.2.27 to a melanoma-associated antigen against a panel of glutaraldehyde-fixed cells, and gave similar binding specificity as assessed by a previous 125I-Protein A assay. Utilizing a unique "sandwich" format, aMr 100,000 melanoma-carcinoma-associated antigen was quantitated in melanoma patient sera and found highly elevated in Stage IV disease. The same sandwich format was also used to detect and determine the class of human immunoglobulin associated with circulating Mr 100,000 human melanoma-associated antigens in normal donor sera. Thus, the sensitivity and flexibility of this enzyme-linked immunosorbent assay system make it particularly suitable for numerous applications in the study of monoclonal antibody-defined tumor-associated antigens.     

Serological response to measles revaccination in a highly immunized military dependent adolescent population

In the spring of 1986, there was a measles outbreak in the city of El Paso, Texas, with 92 cases reported to the City-County Health Department. Of those 92 cases, 31 (32%) occurred within a public high school's student population of 2524. A mass measles vaccination program was undertaken at that high school in order to limit the outbreak. The student enrollment included a military dependent population of 368 students. Despite documented histories of prior measles immunizations in this military dependent subgroup, three individuals contracted the disease. Since this subgroup of students represented a highly immunized adolescent population, it was of interest to serologically determine their immune status prior to and following reimmunization with the expectation that such a study would provide information relating to the level of "protective" immunity. Prevaccination and postvaccination sera were obtained from 95 students. Results of measuring anti-measles antibody activity by ELISA indicate that 13 (14%) students responded to revaccination and experienced a fourfold or greater rise in IgG antibody levels. There were no detectable IgM responses. All of the students who responded to revaccination produced an anamnestic response (IgG boost only). Since most of these individuals had received first immunizations at 15 months of age or older, these findings suggest that secondary vaccine failure (waning immunity) was responsible for the putative "lowered" immunity in these individuals, instead of primary vaccine failure (maternal antibody suppression). These findings support current recommendations for measles booster revaccination of school-age children and adolescents.     

Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2 integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O- tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta2 integrin protein compared with the lower levels of beta2 integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 microg anti-beta2 integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P < 0.01 anti- beta2 integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta2 integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8- OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2 integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as anti-promoting and anti-progression agents.