Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

We investigated whether Rad51 overexpression plays a role in soft tissue sarcoma (STS) chemoresistance as well as the regulatory mechanisms underlying its expression. The studies reported here show that Rad51 protein is overexpressed in a large panel of human STS specimens. Human STS cell lines showed increased Rad51 protein expression, as was also observed in nude rat STS xenografts. STS cells treated with doxorubicin exhibited up-regulation of Rad51 protein while arrested in the S-G(2) phase of the cell cycle. Treatment with anti-Rad51 small interfering RNA decreased Rad51 protein expression and increased chemosensitivity to doxorubicin. Because we previously showed that reintroduction of wild-type p53 (wtp53) into STS cells harboring a p53 mutation led to increased doxorubicin chemosensitivity, we hypothesized that p53 participates in regulating Rad51 expression in STS. Reintroduction of wtp53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression. Using luciferase reporter assays, we showed that reconstitution of wtp53 function decreased Rad51 promoter activity. Deletion constructs identified a specific Rad51 promoter region containing a p53-responsive element but no p53 consensus binding site. Electrophoretic mobility shift assays verified activator protein 2 (AP2) binding to this region and increased AP2 binding to the promoter in the presence of wtp53. Mutating this AP2 binding site eliminated the wtp53 repressive effect. Furthermore, AP2 knockdown resulted in increased Rad51 expression. In light of the importance of Rad51 in modulating STS chemoresistance, these findings point to a potential novel strategy for molecular-based treatments that may be of relevance to patients burdened by STS.     

Using Wireless Handheld Computers to Seek Information at the Point of Care: An Evaluation by Clinicians

Objective

To evaluate: (1) the effectiveness of wireless handheld computers for online information retrieval in clinical settings; (2) the role of MEDLINE® in answering clinical questions raised at the point of care.

Design

A prospective single-cohort study: accompanying medical teams on teaching rounds, five internal medicine residents used and evaluated MD on Tap, an application for handheld computers, to seek answers in real time to clinical questions arising at the point of care.

Measurements

All transactions were stored by an intermediate server. Evaluators recorded clinical scenarios and questions, identified MEDLINE citations that answered the questions, and submitted daily and summative reports of their experience. A senior medical librarian corroborated the relevance of the selected citation to each scenario and question.

Results

Evaluators answered 68% of 363 background and foreground clinical questions during rounding sessions using a variety of MD on Tap features in an average session length of less than four minutes. The evaluator, the number and quality of query terms, the total number of citations found for a query, and the use of auto-spellcheck significantly contributed to the probability of query success.

Conclusion

Handheld computers with Internet access are useful tools for healthcare providers to access MEDLINE in real time. MEDLINE citations can answer specific clinical questions when several medical terms are used to form a query. The MD on Tap application is an effective interface to MEDLINE in clinical settings, allowing clinicians to quickly find relevant citations.     

Studies in Emergency Department Data Collection: Shared versus Split Responsibility for Patient Enrollment

OBJECTIVES: To compare patient enrollment in six clinical studies using shared coverage (24 emergency department [ED] rooms-two students share enrollment responsibility) with enrollment using split coverage (12 rooms each per student). The academic associate (AA) program uses undergraduate students to collect data for clinical studies in the ED by providing double coverage 16 hours/day, seven days/week. Prior studies have shown that this system captures >85% of eligible patients. Methods to obtain closer to 100% enrollment are desired. METHODS: During consecutive 15-day periods with the same 24 AAs, the daily ED census, hours of AA coverage, and enrollment in each of six studies were evaluated prospectively in the ED. Data are presented as means with 95% confidence intervals (CIs). RESULTS: There was no difference between the shared and split enrollment periods with respect to hours of AA coverage (30.3 vs. 30.7 hours/day; p = 0.7) or average daily ED census (133.7 vs. 141.8; p = 0.15). Overall, the percentages of ED patients recruited for study participation were not different depending on whether the split versus shared recruitment strategy was used (907 patients recruited out of 2005 ED patients (45.2%; 95% CI = 43.0 to 47.4) vs. 937 of 2127 (44.0%; 95% CI = 41.9 to 46.1). The 95% CI for the 1.2% difference was -1.8% to 4.2%. Patient enrollments in six individual studies were similar regardless of recruitment strategy. Following the 30-day trial, AAs were surveyed: 17 of 24 (71%) found the split strategy to be "more helpful in enrolling subjects," and 20 of 24 (83%) found split strategy helped them "keep better track" of patients. CONCLUSIONS: Study subject enrollment was not affected by the use of either the shared or split responsibility strategy for recruitment. Students generally preferred the split strategy because it was more helpful and easier to monitor. Therefore, this may be the best option for similar student-oriented data collection programs.     

MRI evaluation of not complicated Tailgut cyst: Case report

INTRODUCTION

The Tailgut cyst (cystic hamartoma) is an uncommon congenital disease of presacral retrorectal space and is embryologically part of some forms of enteric cysts. It is a benign malformation, although cases have been described in neoplastic degeneration.

PRESENTATION OF CASE

A caucasian 24 year old female presented shortly after childbirth with hypogastric abdominal discomfort associated with rectal tenderness, bleeding and moderate urinary symptoms for about three weeks. No previous similar episodes were reported. The patient was not suffering from haemorrhoids or inflammatory disease of the gastrointestinal tract.Clinical examination revealed no significant abnormalities or in the perianal area and gluteal surface.Digital rectal examination was suspicious of the presence of a presacral retrorectal mass. However, it could not exclude a trans-sphinteric perianal fistula. There was no fistulous communication with the exterior and the pain seemed to be more pronounced in the rectum.MRI, which has a diagnostic accuracy of 76–100% for the detection of any perianal fistulae, was performed and demonstrated the presence of a retrorectal cystic hamartoma (Tailgut cyst).

DISCUSSION

The most common retrorectal space cystic lesions includes epidermoid cysts, dermoid cysts and enteric cysts. It presents with pelvic pain, and sometimes with local abscess, secondary to a sinus cyst. There can also be a communication between Tailgut cyst and fistula; in the absence of primary infection may develop postinflammatory fibrosis. Radiological investigation is carried out by TRUS, CT and MRI. During MRI, on T1-weighted images, the signal intensity may change from hypointense to hyperintense as protein concentration increases, as well as in the case of bleeding. On T2-weighted images, signal intensity of mucinous fluids can decrease from highly hyperintense to hypointense with increasing protein concentration and viscosity.

CONCLUSION

MRI is a non-invasive useful imaging investigation with high diagnostic accuracy when a retrorectal cyst is suspected. Despite its rarity, Tailgut cyst should be considered, both for acute complications, like infection or bleeding, and for the risk, however infrequent, of neoplastic degeneration.     

Can Lactobacillus acidophilus improve minimal hepatic encephalopathy? A neurometabolite study using magnetic resonance spectroscopy

Background and study aimsMinimal hepatic encephalopathy (MHE) is diagnosed when hepatic patients perform worse on psychometric tests compared to healthy controls. This study aimed to evaluate probiotics as alternative therapy in MHE.Patients and methodsThis is an open-label randomised controlled trial, performed in the Department of Tropical Medicine and Infectious Diseases, Tanta University Hospitals, from March 2010 to January 2012. A total of 90 patients with MHE were allocated by simple randomisation to three parallel equal groups. Group A received lactulose, group B a probiotic (Lactobacillus acidophilus) and group C served as the control. After informed consent, patients were tested for gut micrecology, fasting blood ammonia, liver functions and magnetic resonance spectroscopy (MRS) examination to study brain metabolites, mainly choline (Cho), myo-inositol (mI), glutamine + glutamate (Glx) and creatinin (Cre). Patients who developed overt encephalopathy were excluded from analysis. The whole battery of investigations was repeated in the same order after 4 weeks.ResultsThe probiotic was better tolerated than lactulose. The relative risk reduction (RRR) of developing overt encephalopathy was 60% in the case of lactulose and 80% in the case of probiotic, with a number needed to treat (NNT) of 2.4 and 2.3, respectively. The differential but not total microecology count was significantly shifted towards saccharolytic rather than proteolytic bacteria. The mI/Cre and (Cho + mI)/Glx ratios were significantly increased and the Glx/Cre ratio was significantly reduced after 1 month-follow-up in the probiotic group compared to the lactulose group and in both treatment groups compared to the control group.ConclusionBoth probiotic and lactulose therapy can improve blood ammonia and psychometric tests in MHE and reduce the risk of developing overt encephalopathy. MRS showed more improvement in the levels of brain neurometabolites in the probiotic group.     

Incidental vascular findings on CT pulmonary angiography (CTPA)

Background:

CT pulmonary angiography (CTPA) is being used increasingly as a diagnostic modality for patients with suspected pulmonary embolism (PE). CTPA frequently reveals incidental findings that may explain the patient’s presentation. These findings could be parenchymal, pleural, or vascular. The aim of this study was to evaluate the spectrum of incidental vascular findings and their significance.

Methods

A retrospective review was done on 508 CTPAs of adults with suspicion of PE in the University of Missouri between June and December of 2009. Forty-three scans were excluded because of motion artifacts or poor contrast. Of the total 465 scans, 39% (180/465) scans were done in the emergency room.

Results

Calcification of the aorta and coronary arteries was the most common finding 27% (124/465), followed by dilatation of the pulmonary trunk 3.4% (16/465) and thoracic aortic aneurysms 1.5% (7/465). Four cases of aberrant right subclavian artery were found. The rest of the findings were rare and were detected in only one or two patients.

Conclusion

CTPA delineates vascular findings other than PE. The majority of these findings are not acute, but warrant recognition and follow up. In less than 1% of the cases, aortic dissection is detected, which might explain the patient’s presentation.