Transcatheter pelvic arterial embolisation for control of obstetric and gynaecological haemorrhage.

We present a 5-year experience of pelvic arterial embolisation at two centres in the UK, and emphasise the role of interventional radiology in the treatment of obstetric and gynaecological haemorrhage. A total of 31 women underwent pelvic embolization:19 patients had complete medical records, and of these, two women had antepartum haemorrhage, 12 women had primary postpartum haemorrhage (PPH), four women had secondary PPH and one woman had a haemorrhage following termination of pregnancy (TOP). The source of the haemorrhage was only identified in four women (21.1%). All patients underwent selective embolisation of the uterine artery or anterior divisional branch of the internal iliac artery with successful haemorrhage control in 17 patients (89.4%) and no immediate complications. Haemorrhage continued despite embolisation in two patients; both proceeded to surgery. Selective pelvic embolisation is a safe and effective treatment for acute obstetric or gynaecological haemorrhage and should be part of the management algorithm for PPH.

Urinary tract stones--Part I: role of radiological imaging in diagnosis and treatment planning.

The modern management of urolithiasis requires a multi-disciplinary approach. Imaging plays a central role in both diagnosis and planning therapy of renal and ureteric calculi. This article reviews the current status of diagnosis and management of stone disease, and the contribution of radiological imaging in accurately triaging a given case to the most appropriate therapy.

Urinary tract stones--Part II: current status of treatment.

The majority of renal and ureteric stones are now managed by minimally invasive techniques, for example nephrostomy, ureteral stents, extracorporeal shockwave lithotripsy or percutaneous nephrolithotomy. A multi-disciplinary approach is necessary, and this review examines the status of modern stone therapy and the contribution of the radiology department.

Demonstration of renal arterial anatomy and tumour neovascularity for vascular mapping of renal cell carcinoma: the value of CO2 angiography.

The aim of this study was to compare the efficacy of CO(2) angiography with that of iodinated contrast angiography for vascular mapping prior to partial nephrectomy for presumed renal cell carcinoma. 13 consecutive patients were studied and all patients underwent selective renal angiography using both CO(2) and iodinated contrast medium. Digitally subtracted images were acquired and compared. Seven male and six female patients, with a median age of 58 years (range 46-74 years), were examined. On comparing images the main renal artery was visualized in all cases with both contrast agents. The segmental vessels were seen in 7 of 13 CO(2) studies and 12 of 13 iodinated contrast studies. CO(2) was also inferior in the depiction of tumour circulation, showing it in 4 of 13 cases compared with 9 of 13 cases using iodinated contrast. It therefore appears that CO(2) angiography offers no diagnostic advantage and is also inferior to iodinated contrast angiography in the pre-operative vascular mapping of renal tumours.

Review of readmissions due to complications from uterine fibroid embolization.

AIM: To determine the frequency, nature and outcome of complications resulting in readmission to hospital following uterine artery embolization (UAE). MATERIAL AND METHODS: A retrospective review of the medical notes and available imaging of 42 consecutive patients who had undergone elective uterine artery embolization for the treatment of fibroid disease was performed. RESULTS: The mean age of the patients was 42 years (range 31--54 years) and seven patients (17%) were readmitted to hospital. The median time to readmission was 3 weeks (range 1-29 weeks). All seven patients were admitted with signs and symptoms of infection. In four patients an organism was isolated from high vaginal swabs, and in one patient the midstream urine sample was confirmed as the source of infection. In the other two patients no definite source of infection was identified. All patients were treated with intravenous antibiotics. Six of the seven patients responded to treatment. The remaining patient required hysterectomy for uncontrolled uterine sepsis. CONCLUSION: Readmission following UAE is common and arises secondary to infection. Infection can occur several months after the procedure.

Renal transplantation dysfunction: the role of interventional radiology.

The aim of this article is to review the radiological management of complications following renal transplant.

Reduction of Cdc25A contributes to cyclin E1-Cdk2 inhibition at senescence in human mammary epithelial cells.

Replicative senescence may be an important tumor suppressive mechanism for human cells. We investigated the mechanism of cell cycle arrest at senescence in human mammary epithelial cells (HMECs) that have undergone a period of 'self-selection', and as a consequence exhibit diminished p16INK4A levels. As HMECs approached senescence, the proportion of cells with a 2N DNA content increased and that in S phase decreased progressively. Cyclin D1-cdk4, cyclin E-cdk2 and cyclin A-cdk2 activities were not abruptly inhibited, but rather diminished steadily with increasing population age. In contrast to observations in fibroblast, p21Cip1 was not increased at senescence in HMECs. There was no increase in p27Kip1 levels nor in KIP association with targets cdks. While p15INK4B and its binding to both cdk4 and cdk6 increased with increasing passage, some cyclin D1-bound cdk4 and cdk6 persisted in senescent cells, whose inhibition could not be attributed to p15INK4B. The inhibition of cyclin E-cdk2 in senescent HMECs was accompanied by increased inhibitory phosphorylation of cdk2, in association with a progressive loss of Cdc25A. Recombinant Cdc25A strongly reactivated cyclin E-cdk2 from senescent HMECs suggesting that reduction of Cdc25A contributes to cyclin E-cdk2 inhibition and G1 arrest at senescence. Although ectopic expression of Cdc25A failed to extend the lifespan of HMECs, the exogenous Cdc25A appeared to lack activity in these cells, since it neither shortened the G1-to-S phase interval nor activated cyclin E-cdk2. In contrast, in the breast cancer-derived MCF-7 line, Cdc25A overexpression increased both cyclin E-cdk2 activity and the S phase fraction. Thus, mechanisms leading to HMEC immortalization may involve not only the re-induction of Cdc25A expression, but also activation of this phosphatase.

Deregulation of the cell cycle in cancer.

Mitogenic and growth-inhibitory signals influence cell-cycle progression through their action on a family of cyclin-dependent kinases (cdks). The activity of cdk complexes is regulated in part by the association of a cyclin partner that acts as a positive effector and by two families of cdk inhibitors, the kinase inhibitor proteins (KIP) and the inhibitors of cdk4 (INK4), which act as negative effectors. In human malignancies, increased expression of cyclins is frequently observed. Cyclin D1 and E are frequently overexpressed in breast cancers, and cyclin E overexpression has been correlated with a poor prognostic outcome. The abrogated expression or the acquisition of mutations that render cdk inhibitors functionally inactive have similarly been found in human malignancies. The p16 gene is frequently deleted or mutated in cancers. Although normal epithelial cells express high levels of p27 protein, reduced levels of p27 have been observed in several human cancers, and this has been consistently correlated with a poor prognostic outcome. In this review, we will provide a brief overview of the cell cycle regulators and then discuss their deregulation in cancers.

p16INK4A mediates cyclin dependent kinase 4 and 6 inhibition in senescent prostatic epithelial cells.

The senescence checkpoint constrains the proliferative potential of normal cells in culture to a finite number of cell doublings. In this study, we investigated the mechanism of cyclin dependent kinase (cdk) inhibition in senescent human prostatic epithelial cells (HPECs). Progression of HPECs from early passage to senescence was accompanied by a gradual loss of cells in S phase and an accumulation of cells containing 2N DNA. Furthermore, G1-S phase-associated kinase activities progressively diminished with increasing cell passage. In senescent HPECs, cdk4 and cyclin E1- and A-associated kinases were catalytically inactive. In contrast to observations in senescent fibroblasts, levels of the kinase inhibitor protein (KIP) inhibitor p21CIP1 diminished over the proliferative life span of HPECs. p27KIP1 levels fell as cells approached senescence, and the association of both p21CIP1 and p27KIP1 with cdk4/6 complexes was decreased. However, the level of cyclin E1-associated KIP molecules was unaltered as cells progressed into senescence. Progression to senescence was accompanied by a progressive increase in both the level of p16(INK4A) and in its association with cdk4 and cdk6. As HPECs approached senescence, cdk4- and cdk6-bound p16(INK4A) showed a shift to a slower mobility due to a change in its phosphorylation profile. As p16(INK4A) increased in cdk4 and cdk6 complexes, there was a loss of cyclin D1 binding. The altered phosphorylation of p16(INK4A) in senescent prostatic epithelial cells may facilitate its association with cdk4 and cdk6 and play a role in the inactivation of these kinases.

Using CO2-enhanced arteriography to investigate acute gastrointestinal hemorrhage.

OBJECTIVE: The objective of the study was to compare the efficacy of CO2-enhanced arteriography with that of arteriography enhanced with standard iodinated contrast material in the detection of gastrointestinal hemorrhage. CONCLUSION: For acute gastrointestinal hemorrhage, we did not find an advantage to using CO2 to show active bleeding. In fact, CO2 was inferior to iodinated contrast material in revealing nonbleeding vascular anomalies.

Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells.

The effects of transforming growth factor beta (TGF-beta) were studied in closely related human mammary epithelial cells (HMEC), both finite-life-span 184 cells and immortal derivatives, 184A1S, and 184A1L5R, which differ in their cell cycle responses to TGF-beta but express type I and type II TGF-beta receptors and retain TGF-beta induction of extracellular matrix. The arrest-resistant phenotype was not due to loss of cyclin-dependent kinase (cdk) inhibitors. TGF-beta was shown to regulate p15INK4B expression at at least two levels: mRNA accumulation and protein stability. In TGF-beta-arrested HMEC, there was not only an increase in p15 mRNA but also a major increase in p5INK4B protein stability. As cdk4- and cdk6-associated p15INK4B increased during TGF-beta arrest of sensitive cells, there was a loss of cyclin D1, p21Cip1, and p27Kip1 from these kinase complexes, and cyclin E-cdk2-associated p27Kip1 increased. In HMEC, p15INK4B complexes did not contain detectable cyclin. p15INK4B from both sensitive and resistant cells could displace in vitro cyclin D1, p21Cip1, and p27Kip1 from cdk4 isolated from sensitive cells. Cyclin D1 could not be displaced from cdk4 in the resistant 184A1L5R cell lysates. Thus, in TGF-beta arrest, p15INK4B may displace already associated cyclin D1 from cdks and prevent new cyclin D1-cdk complexes from forming. Furthermore, p27Kip1 binding shifts from cdk4 to cyclin E-cdk2 during TGF-beta-mediated arrest. The importance of posttranslational regulation of p15INK4B by TGF-beta is underlined by the observation that in TGF-beta-resistant 184A1L5R, although the p15 transcript increased, p15INK4B protein was not stabilized and did not accumulate, and cyclin D1-cdk association and kinase activation were not inhibited.

New functional activities for the p21 family of CDK inhibitors.

The association of cdk4 with D-type cyclins to form functional kinase complexes is comparatively inefficient. This has led to the suggestion that assembly might be a regulated step. In this report we demonstrate that the CDK inhibitors p21(CIP), p27(KIP), and p57(KIP2) all promote the association of cdk4 with the D-type cyclins. This effect is specific and does not occur with other cdk inhibitors or cdk-binding proteins. Both in vivo and in vitro, the abundance of assembled cdk4/cyclin D complex increases directly with increasing inhibitor levels. The promotion of assembly is not attributable to a simple cell cycle block and requires the function of both the cdk and cyclin-binding domains. Kinetic studies demonstrate that p21 and p27 lead to a 35- and 80-fold increase in K(a), respectively, mostly because of a decrease in K(off). At low concentrations, p21 promotes the assembly of active kinase complexes, whereas at higher concentrations, it inhibits activity. Moreover, immunodepletion experiments demonstrate that most of the active cdk4-associated kinase activity also associates with p21. To confirm these results in a natural setting, we examine the assembly of endogenous complexes in mammary epithelial cells after release from a G(0) arrest. In agreement with our other data, cyclin D1 and p21 bind concomitantly to cdk4 during the in vivo assembly of cdk4/cyclin D1 complexes. This complex assembly occurs in parallel to an increase in cyclin D1-associated kinase activity. Immunodepletion experiments demonstrate that most of the cellular cyclin D1-associated kinase activity is also p21 associated. Finally, we find that all three CIP/KIP inhibitors target cdk4 and cyclin D1 to the nucleus. We suggest that in addition to their roles as inhibitors, the p21 family of proteins, originally identified as inhibitors, may also have roles as adaptor proteins that assemble and program kinase complexes for specific functions.

Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer.

Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation. p27Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G1 into S phase by binding and inhibiting cyclin/cdks. p27Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-beta (TGF-beta) and, thus, provide an important link between extracellular regulators and the cell cycle. Loss of p27Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27Kip1 mutations in human tumors are extremely rare. We have demonstrated by immunohistochemistry that p27Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G1/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.