The transcriptional modulator BCL6 as a molecular target for breast cancer therapy.

Inappropriate expression or activation of transcription factors can drive patterns of gene expression, leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we used chromatin immunoprecipitation followed by deep sequencing to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared with B-cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a signal transducer and activator of transcription3 inhibitor provided enhanced cell killing in triple-negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer.

Application of synchrotron microprobe methods to solid-phase speciation of metals and metalloids in house dust.

Determination of the source and form of metals in house dust is important to those working to understand human and particularly childhood exposure to metals in residential environments. We report the development of a synchrotron microprobe technique for characterization of multiple metal hosts in house dust. We have applied X-ray fluorescence for chemical characterization and X-ray diffraction for crystal structure identification using microfocused synchrotron X-rays at a less than 10 µm spot size. The technique has been evaluated by application to archived house dust samples containing elevated concentrations of Pb, Zn, and Ba in bedroom dust, and Pb and As in living room dust. The technique was also applied to a sample of soil from the corresponding garden to identify linkages between indoor and outdoor sources of metals. Paint pigments including white lead (hydrocerussite) and lithopone (wurtzite and barite) are the primary source of Pb, Zn, and Ba in bedroom dust, probably related to renovation activity in the home at the time of sampling. The much lower Pb content in the living room dust shows a relationship to the exterior soil and no specific evidence of Pb and Zn from the bedroom paint pigments. The technique was also successful at confirming the presence of chromated copper arsenate treated wood as a source of As in the living room dust. The results of the study have confirmed the utility of this approach in identifying specific metal forms within the dust.

Nebraska experience.

Nebraska agencies and public health organizations collaboratively addressed cyanobacterial issues for the first time after two dogs died within hours of drinking water from a small private lake south of Omaha on May 4, 2004. A necropsy on one of the dogs revealed that the cause of death was due to ingestion of Microcystin toxins. Within two weeks after the dog deaths, state and local officials jointly developed strategies for monitoring cyanobacterial blooms and issuing public health alerts and advisories. Weekly sampling of public lakes for microcystin toxins and cyanobacteria was initiated during the week of May 17, 2004. ELISA laboratory equipment and supplies were purchased to achieve a quick turnaround time for measuring weekly lake samples for total microcystins so that public health advisories and alerts could be issued prior to each weekend's recreational activities. A conservative approach was selected to protect human health, pets, and livestock, which included collecting worst-case samples from cyanobacterial blooms; freezing and thawing of samples to lyse algal cells and release toxins prior to laboratory analysis; and using action levels of 15 ppb and 2 ppb of total microcystins, respectively, for issuing health alerts and health advisories. During 2004, five dog deaths, numerous wildlife and livestock deaths, and more than 50 accounts of human skin rashes, lesions, or gastrointestinal illnesses were reported at Nebraska lakes. Health alerts were issued for 26 lakes and health advisories for 69 lakes. Four lakes were on health alert for 12 or more weeks. The primary cyanobacterial bloom-forming genera identified in Nebraska lakes were Anabaena, Aphanizomenon, and Microcystis. Preliminary assessments of lake water quality data indicated that lower lake levels from the recent drought and low nitrogen to phosphorus ratios may have contributed, in part, to the increased numbers of cyanobacterial complaints and problems that occurred in 2004.

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas.

Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high inter-species homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

Vasectomy management in Morecambe Bay NHS Trust.

INTRODUCTION: Vasectomy is a common method of contraception in the UK. However, there is a wide variation in management protocols. The aim of the present study was to identify differences within the hospitals of Morecambe Bay NHS Trust and to recommend a uniform practice. PATIENTS AND METHODS: Retrospective case notes review of 395 vasectomy procedures performed within the Morecambe Bay NHS Trust in a 1-year period. RESULTS: Inconsistency was found with regards to the anaesthetic technique, the vas histology request and the timing of the semen analysis. The non-compliance rate for postvasectomy semen analysis was 33.4%. The complication and failure rates were 4.04% and 0.51%, respectively. Motile sperm (n = 4) was submitted at an average time of 8 weeks' postvasectomy. In half of those cases, vasectomy proved unsuccessful. Immotile sperm (n = 41) was submitted at an average time of 9.5 weeks and, in 80% of those men, semen cleared at an average time of 15.5 weeks' postvasectomy. An azoospermic (n = 285) sample was submitted at an average time of 10.5 weeks. Eleven of those men submitted a second sample with immotile sperm at an average time of 12 weeks' postvasectomy and that was eventually clear at 18 weeks in the majority of cases. CONCLUSIONS: A uniform vasectomy practice should include vasectomy under local anaesthesia if possible, no vas histology and a request for a single sample at 12 weeks. If this is clear, vasectomy should be considered successful. If any sperm are present, then a further sample should be requested at 16 weeks' postvasectomy. Immotile sperm at that time should not justify any further samples and a 'special clearance' should be issued to those men.

Techniques for the endovascular management of complications following lower limb percutaneous transluminal angioplasty.

OBJECTIVES: to determine the incidence of early complications following percutaneous transluminal angioplasty and to describe their management and outcome. MATERIALS: five hundred and fifty consecutive patients undergoing angioplasty of 648 limbs, containing 1053 anatomical segments during a two year period were reviewed retrospectively. RESULTS: early complications affected 109 segments (10%) in 92 limbs (14%) of 84 patients (15%). Of the 109 segments affected by early complications, 106 (97%) were managed by endovascular techniques with surgery being required on only three (3%) occasions. There were no deaths attributable to angioplasty. CONCLUSIONS: although early complications occur in 14% of limbs undergoing percutaneous transfemoral angioplasty, the majority (97%) can be managed by endovascular techniques.

Subintimal angioplasty of native vessels in the management of occluded vascular grafts.

OBJECTIVES: to assess the results of subintimal angioplasty of native vessels in the presence of an occluded vascular bypass graft. DESIGN: retrospective case note review. MATERIALS: twelve patients presenting with symptoms of lower limb ischaemia who had previously undergone infra-inguinal bypass surgery and in whom the bypass graft had occluded. These patients were treated by attempting subintimal angioplasty of the occluded native vessels. RESULTS: there were seven technically successful procedures but after a median follow up of four weeks, only one case had persistent patency of the previously occluded segment. CONCLUSIONS: although subintimal angioplasty of occluded native vessels in the presence of an occluded bypass graft appears attractive, the results are disappointing.

Sigmoid ischemia and the inflammatory response following endovascular abdominal aortic aneurysm repair.

PURPOSE: To assess the relationship between sigmoid colonic perfusion, endotoxemia, and cytokine generation in patients undergoing elective open repair (OR) or endovascular repair (EVR) of infrarenal abdominal aortic aneurysms (AAA). METHODS: Ten patients (9 males; average age 67.6 +/- 2.5 years, mean aneurysm diameter 6.9 +/- 0.6 cm) undergoing OR were compared to 10 patients (all males; average age 70.3 +/- 2.6 years, mean aneurysm diameter 6.5 +/- 0.5 cm) whose repair was performed using the EVR technique. The partial pressure of the carbon dioxide gap (PCO2gap = tissue PCO2 - arterial PCO2) of the sigmoid colonic mucosa was measured using a silicone tonometer to evaluate bowel perfusion. Blood samples were collected into pyrogen-free heparinized tubes for quantification of plasma concentrations of endotoxin, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) before, during, and after aortic repair. RESULTS: Patients in the OR group had a significantly greater increase in PCO2gap, suggesting a greater degree of bowel ischemia compared to the EVR group. This was associated with significantly greater postoperative concentrations of endotoxin, TNF-alpha, and IL-6 in the OR group. A significant correlation was found between PCO2gap, IL-6, and postoperative core temperature. CONCLUSIONS: The results suggest that the degree of bowel ischemia, endotoxemia, and cytokine generation following elective infrarenal AAA reconstruction may be reduced if the endovascular technique is used instead of conventional surgery.

Mortality rates following endovascular repair of abdominal aortic aneurysms.

PURPOSE: To present the perioperative and late mortality following endovascular repair (EVR) of abdominal aortic aneurysms (AAAs). METHODS: Data were collected prospectively on 221 patients undergoing AAA EVR over a 4-year period (median 5-month follow-up). Patients were classified preoperatively as high risk with at least 1 of these features: serum creatinine > 150 micromol/L, ischemic heart disease or poor left ventricular function, respiratory function < 50% of predicted normal, ruptured or symptomatic AAA, contraindication to or failed open repair, and age > 80 years. RESULTS: One hundred forty (63.3%) patients were classified as high risk, the most common criterion being cardiac disease (n = 96, 68.6%). There were 25 (11.3%) deaths in the 30-day perioperative period, 22 (15.7%) in the high-risk group compared to 3 (3.7%) in the acceptable-risk group (p = 0.02). The most common causes of perioperative death were multisystem organ failure and myocardial infarction. A further 21 (9.5%) late deaths occurred, 16 (11.4%) in the high-risk group and 5 (6.2%) in the acceptable-risk group (p > 0.1). CONCLUSIONS: The mortality of patients at acceptable risk undergoing EVR compares with the best published series for conventional open AAA repair. The perioperative and late mortality in the high-risk patients are substantially higher.

Peripheral thrombolysis for acute-onset claudication. Thrombolysis Study Group.

BACKGROUND: The aim of this study was to determine the outcome of patients who presented with sudden onset of incapacitating claudication of less than 2 weeks' duration and who were treated with peripheral arterial thrombolysis. METHODS: The database of the Thrombolysis Study Group was searched retrospectively for patients who received thrombolysis for acute-onset claudication. Some 108 patients (65 men, median age 69 (range 29-94) years) were treated with intra-arterial tissue plasminogen activator at 14 hospitals. The median duration of symptoms was 72 h (range from 2 h to 2 weeks). There were 52 graft and 56 native vessel arterial occlusions. RESULTS: The immediate outcome of thrombolysis for native vessel arterial occlusion was thrombus clearance in 50 patients (89 per cent) and failed lysis in six (11 per cent). Thirty-six patients (64 per cent) had a secondary radiological or surgical procedure carried out after lysis. After 30 days four patients (7 per cent) had a major amputation, eight (14 per cent) had died, 38 (68 per cent) were symptom free and seven (12 per cent) continued to have claudication. Three patients (5 per cent) suffered a major haemorrhage. The immediate outcome of thrombolysis for graft occlusion was thrombus clearance in 48 patients (92 per cent) and failed lysis in four (8 per cent); 27 patients (52 per cent) had a secondary procedure. After 30 days four patients (8 per cent) had a major amputation, seven (13 per cent) had died, 32 (62 per cent) were symptom free and nine (17 per cent) had persistent claudication. Three patients (6 per cent) suffered a major haemorrhage. CONCLUSION: Patients who presented with acute onset of incapacitating claudication had an outcome similar to that after thrombolysis for critical ischaemia. It is recommended that patients who present in this way should be observed and treated with thrombolysis only if they progress to critical ischaemia. Presented to the Association of Surgeons of Great Britain and Ireland, Edinburgh, UK, May 1998, and published in abstract form as Br J Surg 1998; 85(Suppl 1): 24

A prospective study to assess changes in proximal aortic neck dimensions after endovascular repair of abdominal aortic aneurysms.

OBJECTIVE: The purpose of this study was to detect any change in the proximal neck diameter after endovascular repair of abdominal aortic aneurysm. METHODS: The study was performed in a teaching hospital with an endovascular program on 112 patients who had undergone endovascular repair of abdominal aortic aneurysm. The interventions were pre-endovascular and postendovascular repair of abdominal aortic aneurysms with contrast-enhanced, spiral computerized tomography, and the main outcome measures were change in aortic proximal neck diameter, change in maximum aortic diameter, presence of endoleaks, and change in length from lowest renal artery to aortic bifurcation. RESULTS: The median anterior-posterior and transverse diameter decreased from 63.5 mm before surgery to 50.4 and 54.5 mm, respectively, after surgery in a period of 4 years. This trend in reduction in maximum diameter was not seen in the patients with endoleaks. There was no significant change in the proximal neck diameters when measured at 5-mm intervals after endovascular repair. There was also no significant change in the aortic length after endovascular repair. CONCLUSION: We have not demonstrated any evidence for proximal neck dilatation after endovascular repair of abdominal aortic aneurysm.

Endovascular AAA repair: prevention of side branch endoleaks with thrombogenic sponge.

PURPOSE: To report a technique that might decrease the incidence of lumbar artery endoleaks following endovascular repair (EVR) of abdominal aortic aneurysms (AAAs). METHODS: Ninety-three patients (86 males, median age 72 years, range 56 to 88) undergoing EVR with the aortomonoiliac technique were entered into a study to detect and then occlude patent side branches before completion of the endografting procedure. Prior to deploying the iliac occluder, an aneurysmogram was performed to detect patent aortic side branches. If these side branches were found, an absorbable gelatin sponge was inserted into the aneurysm sac via the occluder introducer sheath. The patients were followed with contrast-enhanced spiral computed tomography (CT) at 1 week and 3, 6, and 12 months to detect the presence of endoleaks. RESULTS: Forty-eight (52%) patients demonstrated patent side branches that were occluded by the insertion of gelatin sponges into the aneurysm sac. The remaining 45 patients without evidence of side branch flow were untreated. Ten (10.7%) patients died in the perioperative period, and 15 (16.1%) primary endoleaks (13 proximal, 2 distal) were detected. This left 68 (73.1%) patients for follow-up, 33 (48.5%) of whom had patent branch vessels treated with the thrombogenic sponge. The median follow-up was 4 months (range 1 to 17), during which time no side branch endoleak was detected on surveillance CT scans in any of the 68 patients, which included all patients treated with the thrombogenic sponge technique and those in whom no patent side branches had been identified. CONCLUSIONS: We have demonstrated a safe and reliable method of preventing lumbar artery endoleaks following endovascular AAA repair.

Blood product requirements in patients undergoing elective endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Endovascular repair (EVR) of abdominal aortic aneurysm (AAA) has many potential advantages, one of which may be reduced blood product requirements. The aim of this study was to compare the current blood product usage in our unit for three types of elective operation: EVR of AAA, open AAA repair and femorofemoral crossover grafts. DESIGN: Prospective data analysis with historical controls. MATERIALS: One-hundred and thirty-two patients undergoing elective EVR of AAA, 35 patients undergoing elective open repair of AAA and 37 patients having femorofemoral crossover grafts. METHODS: Data was collected on the blood product requirements of patients having EVR of AAA, with open AAA repair and femorofemoral crossover graft providing historical controls. RESULTS: There was no difference in the haematological parameters preoperatively between the three groups but postoperatively patients having EVR had a slightly lower haemoglobin than the open group (10.6 g/dl vs. 10.85 g/dl, p = 0.015). The number of patients who received blood transfusion in the EVR group was 82/132 (62%) and the open group 27/35 (77%), p = 0.4. CONCLUSION: Patients undergoing EVR of AAA require blood transfusion in the same numbers when compared to those undergoing open repair.

Renal complications following endovascular repair of abdominal aortic aneurysms.

PURPOSE: To investigate the renal complications associated with endovascular repair of abdominal aortic aneurysms (AAAs). METHODS: Data were prospectively collected on 164 AAA patients (154 males; median age 72 years; interquartile range 51 to 88) undergoing endovascular grafting. Any history of renal failure and diabetes mellitus was recorded. Serum urea and creatinine levels were measured preoperatively and at regular intervals postoperatively. Renal impairment was defined as serum creatinine > 130 micromol/L. RESULTS: There were no significant differences in pre- and 1-day postoperative serum urea and creatinine levels. Among 15 (9.1%) patients with preoperative renal failure, 7 (47%) died, 4 (27%) in the perioperative period. Of the 149 patients with normal renal function preoperatively, 4 (2.7%) developed renal failure as part of multisystem organ failure. Another 9 (6.2%) developed significant postoperative elevations (> 20%) in their creatinine levels compared to baseline; 4 of these patients died, 2 in the perioperative period. There was no significant difference in the median dose of intravascular contrast used for those patients that did and did not have a deterioration in their renal function (250 mL versus 300 mL). CONCLUSIONS: In this study, approximately 6% of patients with normal preoperative renal function who undergo endovascular AAA repair develop renal dysfunction. For patients with preoperative renal impairment, the perioperative mortality rate is high, 27%, following endovascular aortic aneurysm repair.

A randomized, double-blind, placebo-controlled, crossover study to assess the immediate effect of sublingual glyceryl trinitrate on the ankle brachial pressure index, claudication, and maximum walking distance of patients with intermittent claudication.

PURPOSE: The goal of the present study was to assess the immediate effect of sublingual glyceryl trinitrate (GTN) in patients with intermittent claudication. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover study. Inclusion criteria consisted of history of intermittent claudication, resting ankle brachial pressure index (ABPI) of 1.00 or less, a 20% or greater fall in ABPI after exercise, and maximum walking distance (MWD) of less than 250 m. Patients already receiving nitrates were excluded. In study 1, patients (n = 25) underwent a standard exercise test after randomization to receive either 800 microg of sublingual GTN or placebo. The postexercise ABPI was recorded. Then, the crossover portion of the study was performed. In study 2, patients (n = 22) had their claudication distance and MWD measured. They then were randomized to receive either GTN or placebo spray, and the exercise test was repeated, with the claudication distance and MWD recorded, followed by the crossover portion of the study. Statistical analysis was performed with the Wilcoxon matched pairs signed ranks test and the Mann-Whitney U test. RESULTS: In study 1, the median postexercise ABPIs for placebo and GTN were 0.29 and 0.36 (P =.0001). In study 2, the median claudication distance for both placebo and GTN groups was 70 m (P =.59). The median MWD for the placebo and GTN groups was 105 and 125 m (P =.0084) CONCLUSION: GTN can decrease the fall in ABPI after exercise and increase the MWD.

A randomized controlled trial comparing a 21 G needle with a 23 G needle for fine needle aspiration of breast lumps.

A randomized study was performed on patients in whom the clinical decision had already been made to excise a breast lump. The objective was to assess the difference in diagnostic results of 21 and 23 G needles in the fine needle aspiration cytology (FNAC) of breast lumps. Following induction of anaesthetic, (local or general), FNAC was performed with either a 21 or 23 G needle. The breast lump was then excised and the histology and cytology results analysed routinely. One hundred and twenty-five excised breast lumps were included. Sixty-one had FNAC performed with a 21 G needle and 64 had FNAC performed with a 23 G needle. Of the 61 21 G FNAC, histology revealed 45 breast cancers. Of the 64 23 G FNAC, 50 patients had breast cancer. There was no statistical difference between these two results. There is no difference in the cytological yield when a 21 G needle is compared with that of a 23 G needle.