Use of the X-SIXER catheter system in the treatment of acute thrombotic coronary occlusion

The X-SIZER thromboatherectomy catheter system (EndiCOR Medical, Inc.) was initially developed for the treatment of thrombus in acute coronary syndromes. We present the case of a 64-year-old man with thrombotic occlusion of the left circumflex coronary artery. Antegrade flow was restored by aspiration of platelet thrombus at the point of occlusion, although the catheter was unable to cross the underlying stenosis. Its limited ability to cross severe stenoses or reduce lesion severity suggests that the X-SIZER should not be regarded as an atherectomy device. However, this case report suggests that the X-SIZER device has potential as an adjunct to PTCA and stenting in reducing the risk associated with thrombotic occlusion.     

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

Despite successful control of viremia, many HIV-infected individuals given antiretroviral therapy (ART) exhibit residual inflammation, which is associated with non–AIDS-related morbidity and mortality and may contribute to virus persistence during ART. Here, we investigated the effects of IL-21 administration on both inflammation and virus persistence in ART-treated, SIV-infected rhesus macaques (RMs). Compared with SIV-infected animals only given ART, SIV-infected RMs given both ART and IL-21 showed improved restoration of intestinal Th17 and Th22 cells and a more effective reduction of immune activation in blood and intestinal mucosa, with the latter maintained through 8 months after ART interruption. Additionally, IL-21, in combination with ART, was associated with reduced levels of SIV RNA in plasma and decreased CD4⁺ T cell levels harboring replication-competent virus during ART. At the latest experimental time points, which were up to 8 months after ART interruption, plasma viremia and cell-associated SIV DNA levels remained substantially lower than those before ART initiation in IL-21–treated animals but not in controls. Together, these data suggest that IL-21 supplementation of ART reduces residual inflammation and virus persistence in a relevant model of lentiviral disease and warrants further investigation as a potential intervention for HIV infection.     

Fall-related risk factors and osteoporosis in older women referred to an open access bone densitometry service

OBJECTIVE: Both falls and low bone density are important in the pathogenesis of osteoporotic fractures. Whilst bone density is routinely measured to assess fracture risk, little attention is given to the assessment of fall risk. In this study we have determined the prevalence and explored relationships between fall-related risk factors and osteoporosis in women referred to our open access bone densitometry service. DESIGN: Cross-sectional study. SETTING: Teaching hospital in south-west London, UK. SUBJECTS: Older women referred for open access bone densitometry. MEASUREMENTS: Bone densitometry by dual-energy X-ray absorptiometry and fall risk assessment (visual acuity, ability to do five stand-ups without arm use and ability to perform heel-toe walking). RESULTS: Data for 558 women seen over an 18 month period were examined. Their mean age was 74.8 years (range 65-93). Fall risk and femoral neck (FN) osteoporosis increased with age, with fall-related risk factors being more prevalent than FN osteoporosis at each tertile of age. Women with both FN osteoporosis and fall-related risk factors ranged from 7% in the youngest tertile to 22% in the oldest tertile. In women with FN osteoporosis, increased fall risk was found in 37% in the youngest tertile, increasing to 63% in the oldest tertile. CONCLUSIONS: Fall-related risk factors are common in older women referred for open access bone densitometry. We recommend that both bone density and fall risk assessment, using simple screening tests for falls, are essential to determine fracture risk in older people referred for bone densitometry. Subsequent management to reduce fracture risk should be individualised for each patient.     

Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma

To investigate host and viral mechanisms determining hepadnaviral persistence and hepatocarcinogenesis, we developed a mouse model by transplanting woodchuck hepatocytes into the liver of mice that contain the urokinase-type plasminogen activator transgene (uPA) and lack mature B and T lymphocytes due to a recombination activation gene 2 (RAG-2) gene knockout. The woodchuck hepatocytes were transplanted via intrasplenic injection and were found to integrate into the recipient mouse liver cord structure. Normal adult woodchuck hepatocytes proliferated and reconstituted up to 90% of the uPA/RAG-2 mouse liver. uPA/RAG-2 mice containing woodchuck hepatocytes were infectable with woodchuck hepatitis virus (WHV) and showed WHV replication for at least 10 months with titers up to 1 × 10¹¹ virions per ml in the peripheral blood. WHV-infected hepatocytes from chronic carrier woodchucks also established a persistent infection in uPA/RAG-2 mice after an 8- to 12-week lag period of viremia. Although WHV envelope, core, and X proteins were produced in the uPA/RAG-2 mice, no inflammatory host immune response was observed in the liver of WHV-replicating mice. A first antiviral test demonstrated a greater than four orders of magnitude drop in WHV titer in response to interferon α treatment. WHV replication was up-regulated by dexamethasone treatment. Comparison of precancerous lesions in donor woodchucks versus recipient uPA/RAG-2 mice revealed an enrichment of dysplastic precancerous hepatocytes in transplanted mice. Clonal amplification of hepatocytes from a woodchuck with hepatocellular carcinomas was demonstrated by the detection of unique WHV DNA integration patterns in hepatocellular carcinomas that arose in uPA/RAG-2 mice. In the absence of B or T cell-mediated immune responses, WHV establishes a persistent noncytotoxic infection of woodchuck hepatocytes in uPA/RAG-2 chimeric mouse livers. Further studies of the kinetics of hepadnavirus infection and replication in quiescent and proliferating hepatocytes should increase our understanding of hepadnavirus spread and aid in the design of therapies to block or cure persistent infection.     

Amplification and over‐expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells

Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 gene as a potential therapeutic target in breast cancer. This gene encodes mitogen‐activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), which has not yet been reported to be associated with cancer‐causing genetic aberrations. We found that MAP3K3 was amplified in approximately 8–20% of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3‐amplified breast cancer cell lines MCF‐7 and MDA‐MB‐361 but not in MAP3K3 non‐amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3‐amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNFα and TRAIL, as well as doxorubicin, VP‐16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, induced colony formation in both primary mouse embryonic fibroblasts and immortalized human breast epithelial cells (MCF‐10A). Combined, these results suggest that MAP3K3 contributes to breast carcinogenesis and may endow resistance of breast cancer cells to cytotoxic chemotherapy. Therefore, MAP3K3 may be a valuable therapeutic target in patients with MAP3K3‐amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3‐amplified breast cancer cells to chemotherapy. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.