Suspected giant cell arteritis:A study of referrals for temporal artery biopsy

Background: The purpose of this study is to describe the nature of cases undergoing temporal artery biopsy (TAB) for suspected giant cell arteritis (GCA). Methods: A retrospective review of case notes was undertaken for all patients on whom ophthalmologists had performed TAB in 2 teaching hospitals between 1995 and 2001. Presenting symptoms, referring specialty, TAB result, treatment, and discharge diagnosis were recorded. Results: Ophthalmologists performed TAB on 110 patients for suspected GCA. A variety of specialties referred patients to ophthalmology for TAB; presenting symptoms varied with referral source. Of the 110 TABs, 21 (19%) were reported as positive for GCA, 84 (76%) were negative, and 5 (4.5%) were reported as inadequate. The symptoms most commonly associated with a positive TAB were visual disturbance (15/21) and headache (15/21).The odds ratios for having a positive TAB result rather than a negative result were 1.0 for the presence of headache, 4.1 for visual disturbance, and 6.7 for jaw claudication. Interpretation: Physicians were faced with a different population of GCA suspects than ophthalmologists. While physicians should be alert to the significance of visual symptoms or jaw claudication, ophthalmologists should be ready to facilitate prompt TABs when appropriate. TAB should be performed promptly and an adequate length of artery taken for biopsy. An argument can be made that TAB is not needed in cases of suspected GCA. However, a positive result provides firm justification for the use of steroids. We feel that TAB has a useful role and we make reference to methods to maximize its usefulness.

Capsulotomy worsens diabetic retinopathy in the Ins2Akitamice

Purpose: Cataract surgery increases the risk of developing diabetic retinopathy (DR) and accelerates the progression of pre-existing DR. Recent evidence suggests that cataract surgery elicits retinal pro-inflammatory gene expression, although the underlying pathogenic mechanisms remain ill-defined. In this study, we investigated the effect of capsulotomy on visual function, retinal immune cell activation and photoreceptor stress in the Ins2Akita mice, a mouse model of Type-1 diabetes. Methods: Male heterozygous Ins2Akita mice (2 months of hyperglycemia) and C57BL/6J age-matched siblings were used in this study. An incision (1mm) was made in the peripheral cornea and Capsulotomy was performed in the anterior lens capsule of the right eye. Control mice received corneal incision without capsulotomy in the right eye. The unoperated left eyes were used as internal controls. Forty days following surgery, retinal function was assessed by electroretinography (ERG). Neuronal retinal damage and microglial activation were assessed by imunohistochemistry. Results: The Ins2Akita mice receiving capsulotomy presented lower scotopic a-wave, b-wave and oscillatory potentials amplitudes compared to other experimental groups. Fundus images, SD-OCT and H&E staining did not show significant changes between different groups. Immunostaining of Iba-1 and CD68 revealed exacerbated microglial activation and giant cell immune cell infiltration in eyes receiving capsulotomy in Ins2Akita mice. This was accompanied by a disruption of cone photoreceptor outer segments and abnormal rhodopsin expression at the outer nuclear layer. Conclusions: Our results suggest that capsulotomy induces retinal microglial activation and worsens retinal neuropathy in diabetic eyes.

Hematopoietic malignancies associated with viral and alcoholic hepatitis

Hepatitis C virus (HCV) and hepatitis B virus (HBV) have been associated with hematopoietic malignancies, but data for many subtypes are limited. From the U.S. Surveillance, Epidemiology, and End Results-Medicare database, we selected 61,464 cases (=67 years) with hematopoietic malignancies and 122,531 population-based controls, frequency-matched by gender, age, and year (1993-2002). Logistic regression was used to compare the prevalence of HCV, HBV, and alcoholic hepatitis in cases and controls, adjusted for matching factors, race, duration of Medicare coverage, and number of physician claims. HCV, HBV, and alcoholic hepatitis were reported in 195 (0.3%), 111 (0.2%), and 404 (0.7%) cases and 264 (0.2%), 242 (0.2%), and 798 (0.7%) controls, respectively. HCV was associated with increased risk of diffuse large B-cell lymphoma [odds ratio (OR) 1.52, 95% confidence interval (95% CI) 1.05-2.18], Burkitt lymphoma (OR 5.21, 95% CI 1.62-16.8), follicular lymphoma (OR 1.88, 95% CI 1.17-3.02), marginal zone lymphoma (OR 2.20, 95% CI 1.22-3.95), and acute myeloid leukemia (OR 1.54, 95% CI 1.00-2.37). In contrast, HBV was unrelated to any hematopoietic malignancies. Alcoholic hepatitis was associated with decreased risk of non-Hodgkin lymphoma overall, but increased risk of Burkitt lymphoma. In summary, HCV, but not other causes of hepatitis, was associated with the elevated risk of non-Hodgkin lymphoma and acute myeloid leukemia. HCV may induce lymphoproliferative malignancies through chronic immune stimulation. Copyright © 2008 American Association for Cancer Research.


--------------------------------------------------------------------------------

Reaxys Database Information|

--------------------------------------------------------------------------------

Effects of the amphibian skin-derived bradykinin B2 receptor antagonist peptide, kinestatin, on the proliferation of human prostate cancer cell lines

Bradykinin and related peptides are found in the defensive skin secretions of many frogs and toads. While the physiological roles of bradykinin-related peptides in sub-mammalian vertebrates remains obscure, in mammals, including humans, canonical bradykinin mediates a multitude of biological effects including the proliferation of many types of cancer cell. Here we have examined the effect of the bradykinin B2 receptor antagonist peptide, kinestatin, originally isolated by our group from the skin secretion of the giant fire-bellied toad, Bombina maxima, on the proliferation of the human prostate cancer cell lines, PC3, DU175 and LnCAP. The bradykinin receptor status of all cell lines investigated was established through PCR amplification of transcripts encoding both B1 and B2 receptor subtypes. Following this demonstration, all cell lines were grown in the presence or absence of kinestatin and several additional bradykinin receptor antagonists of amphibian skin origin and the effects on proliferation of the cell lines was investigated using the MTT assay and by counting of the cells in individual wells of 96-well plates. All of the amphibian skin secretion-derived bradykinin receptor antagonists inhibited proliferation of all of the prostate cancer lines investigated in a dose-dependent manner. In addition, following incubation of peptides with each cell line and analysis of catabolites by mass spectrometry, it was found that bradykinin was highly labile and each antagonist was highly stable under the conditions employed. Bradykinin signalling pathways are thus worthy of further investigation in human prostate cancer cell lines and the evidence presented here would suggest the testing of efficacy in animal models of prostate cancer as a positive outcome could lead to a drug development programme for the treatment of this disease.

Identification of GSK625433: A novel clinical candidate for the treatment of hepatitis C.

Hepatitis C is an infection of the liver caused by a pos. single-stranded RNA virus (HCV) which affects 170 million people worldwide. It is responsible for 40-60% of all liver disease and is the major cause of liver transplants in the United States. The HCV NS5B gene encodes the viral RNA-dependent RNA polymerase which is essential for HCV replication. We have previously reported the identification of acylpyrrolidines as potent inhibitors of NS5B; however their activity is attenuated against genotype 1a. The design of improved broader-spectrum compds., capable of effective inhibition of both genotypes 1b and 1a is desirable. An understanding of the binding site and genotype sequence differences was utilized to design compds. with greatly enhanced genotype 1a and 1b potency. Our studies led to the identification of GSK625433, a potent, homochiral inhibitor of these HCV genotypes in both enzyme and sub-genomic replicon cell-based assays. GSK625433 has a good pharmacokinetic profile in pre-clin. animal species, enabling progression to clin. evaluation.

C/EBP alpha Is Up-regulated in a Subset of Hepatocellular Carcinomas and Plays a Role in Cell Growth and Proliferation

BACKGROUND & AIMS: C/EBP alpha (cebpa) is a putative tumor suppressor. However, initial results indicated that cebpa was up-regulated in a subset of human hepatocellular carcinomas (HCCs). The regulation and function of C/EBP alpha was investigated in HCC cell lines to clarify its role in liver carcinogenesis. METHODS: The regulation of C/EBP alpha expression was studied by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting, immunohistochemistry, methylation-specific PCR, and chromatin immunoprecipitation assays. C/EBP alpha expression was knocked-down by small interfering RNA or short hairpin RNA. Functional assays included colony formation, methylthiotetrazole, bromodeoxyuridine incorporation, and luciferase-reporter assays. RESULTS: Cebpa was up-regulated at least 2-fold in a subset (approximately 55%) of human HCCs compared with adjacent non tumor tissues. None of the up-regulated samples were positive for hepatitis C infection. The HCC cell lines Hep3B and Huh7 expressed high, PLC/PRF/5 intermediate, HepG2 and HCC-M low levels of C/EBP alpha, recapitulating the pattern of expression observed in HCCs. No mutations were detected in the CEBP alpha gene in HCCs and cell lines. C/EBP alpha was localized to the nucleus and functional in Hep3B and Huh7 cells; knocking-down its expression reduced target-gene expression, colony formation, and cell growth, associated with a decrease in cyclin A and CDK4 concentrations and E2F transcriptional activity. Epigenetic mechanisms including DNA methylation, and the binding of acetylated histone H3 to the CEBP alpha promoter-regulated cebpa expression in the HCC cells. CONCLUSIONS: C/EBP alpha is up-regulated in a subset of HCCs and has growth-promoting activities in HCC cells. Novel oncogenic mechanisms involving C/EBP alpha may be amenable to epigenetic regulation to improve treatment outcomes.

Morphometric analysis of corneal endothelial giant cells in normal and traumatized corneas

Corneal endothelial cells from normal and traumatized human, primate, cat and rabbit eyes were studied by specular microscopy. Morphometric analysis was performed on micrographs of corneal endothelium using a semi-automated image analysis system. The results showed that under normal conditions the corneal endothelium of all four species exhibit major morphological similarities (mean cell areas: human 317 +/- 32 microns 2, primate 246 +/- 22 microns2, cat 357 +/- 25 microns 2, rabbit 308 +/- 35 microns 2). The normal corneal endothelium in man was found to be more polymegethous than that of the other species. Trauma to cat, primate and human corneas resulted in a long-term reduction in endothelial cell density and enhanced polymegethism. In contrast, the reparative response of the rabbit ensured the reformation of an essentially normal monolayer following injury. Endothelial giant cells were a normal inclusion in the rabbit corneal endothelium but were only significant in cat, primate and man following trauma. The presence of corneal endothelial giant cells in amitotic corneas may therefore represent a compensatory response in the absence of mitotic potential.

Genomic lesions associated with a different clinical outcome in diffuse large B-Cell lymphoma treated with R-CHOP-21

Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21_d). 166 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH.