Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯的合成

合成了18个O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯类化合物(Ⅰ_1～18)。初步杀螺试验结果表明,其中5个化合物,即Ⅰ_2,3,7,11,12有明显的杀螺增效作用。     

Circulating T-cell populations during mercuric chloride-induced nephritis in the Brown Norway rat.

Fluorescence-activated cell sorter analysis was used to study the peripheral lymphocyte populations during mercuric chloride (HgCl2)-induced autoimmune nephritis in the Brown Norway (BN) rat. Sequential studies showed a transient loss of T cells from peripheral blood attributable to decreases in the percentage of T-helper cells. In addition, there was a decrease in the percentage of T-cytotoxic/suppressor cells prior to the appearance of circulating anti-GBM antibodies, followed by elevated levels of T-suppressor cells during down-regulation of the response. This method may allow closer inspection of the events linking changes in T-cell populations and induction and termination of an autoimmune response.     

Therapeutic Vaccines for Cervical Cancer

Human papillomavirus (HPV) infection is associated with transformation and clonal expansion of infected epithelial cells, resulting in the production of a benign growth, i.e. a wart. Recently, however, HPV has emerged as the primary causative agent of cervical carcinoma, malignancy being associated with the presence of the viral genome (predominantly genotypes 16 and 18) in cancerous cells. The only HPV proteins reliably expressed in neoplastic lesions are the 'oncogenic' E6 and E7 proteins, that serve both as tumour-specific markers and potential targets for immunotherapeutic intervention. As intracellular (nuclear) proteins, the E6 and E7 gene products may be hidden from the humoral immune response. Attention has thus focused on the generation of a vaccine capable of inducing or stimulating a cellular immune response to HPV 16 and HPV 18 E6 and E7. Vaccine development has been constrained by the absence of an appropriate animal model, the oncogenic nature of E6 and E7 and technical difficulties associated with detection of cytotoxic T cell responses to these antigens. Despite these difficulties, vaccine strategies have now been devised based on immunisation with synthetic peptide, whole protein and a vaccinia virus recombinant. Phase I/II human clinical trials have been initiated, and preliminary results have demonstrated the induction of specific cellular immune responses after immunisation. The HPV-associated neoplasia in cervical cancer represents an excellent target for therapeutic intervention because the tumour-associated antigens are so clearly defined. As such, it provides an appropriate model for establishing the general principles of cancer immunotherapy in humans.     

Novel method for detection, typing, and quantification of human papillomaviruses in clinical samples

We report the development of a novel detection and typing methodology for human papillomaviruses (HPV) based on real-time PCR with the self-probing fluorescent primers known as Scorpions. This technique is quick, simple, specific, sensitive, and capable of estimating viral load per cell. We report the results of over 100 typing reactions performed on cell lines, biopsies, and cervical cytobrush samples which, when compared to the current reference HPV detection and typing technique, present a kappa value of 0.89. We further report preliminary data suggesting a relationship between viral load per cell and grade of cervical disease.     

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Human cytomegalovirus (HCMV) exploits a range of strategies to evade and modulate the immune response. Its capacity to down-regulate MHC I expression was anticipated to render infected cells vulnerable to natural killer (NK) attack. Kinetic analysis revealed that during productive infection, HCMV strain AD169 first enhanced and then inhibited lysis of primary skin fibroblasts by a CD94/NKG2A(+)NKG2D(+)ILT2(+) NK line. The inhibition of cytotoxicity against strain AD169-infected fibroblasts was abolished by prior treatment of targets or effectors with anti-MHC I and anti-CD94 monoclonal antibodies, respectively, implying a CD94/HLA-E-dependent mechanism. An HCMV strain AD169, UL40 deletion mutant could not inhibit CD94/NKG2A(+) NK killing against skin fibroblasts. The contribution of UL40 to evasion of primary NK cells then was tested in a system where targets and effectors were MHC-matched. Primary NK cells activated with IFNalpha as well as cultured primary NK cell lines showed increased killing against DeltaUL40-infected fibroblasts compared with AD169-infected targets. This effect was abrogated by depletion of CD94(+) cells. These findings demonstrate that HCMV encodes a mechanism of evasion specifically targeted against a proportion of CD94(+) NK cells and show that this system functions during a productive infection.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.