Targeting Gonadotropin-releasing Hormone Receptor Inhibits the Early Step of Ovarian Cancer Metastasis by Modulating Tumor-mesothelial Adhesion

Ovarian cancer has a clear predilection to metastasize to the peritoneum, which represents one of the most important prognostic factors of poor clinical outcome. Gonadotropin-releasing hormone (GnRH) receptor is significantly overexpressed during the malignant progression of human ovarian cancer. Here, using lentiviral-based small interfering RNA (siRNA) technology to downregulate GnRH receptor in metastatic ovarian cancer cells, we show that GnRH receptor is an important mediator of ovarian cancer peritoneal metastasis. GnRH receptor downregulation dramatically attenuated their adhesion to the peritoneal mesothelium. By inhibiting the expression of GnRH receptor, we showed decreased expression of α2β1 and α5β1 integrin and adhesion to specific extracellular matrix (ECM) proteins. This was also associated with a reduction of P-cadherin. Furthermore, adhesion of ovarian cancer cells to different ECMs and the mesothelium were abrogated in response to β1 integrin and P-cadherin reduction, confirming that the effects were β1 integrin- and P-cadherin–specific. Using a mouse model of human ovarian cancer metastasis, we found that the inhibition of GnRH receptor, β1 integrin, and P-cadherin significantly attenuated tumor growth, ascites formation, and the number of metastatic implants. These results define a new role for GnRH receptor in early metastasis and offer the possibility of novel therapeutic targets.     

CT angiograms for lower GI bleeding: the experience of a large UK teaching hospital

IntroductionThe clinical presentation of lower gastrointestinal bleeding (LGIB) is variable in severity, cause and potential investigations. The British Society of Gastroenterology recently published LGIB guidelines, recommending CT angiography (CT-A) for haemodynamically unstable patients, defined by shock index (SI) greater than 1. The aim of this study was to assess the use and role of CT-A in diagnosing LGIB, by assessing the pickup rate of active LGIB defined by contrast extravasation or ‘blush’ and to determine any association between positive CT-A with various patient and clinical characteristics.MethodsA retrospective analysis was carried out of 4 years of LGIB admissions. Demographics, inpatient observations and use of blood products were acquired. Vital signs nearest the time of CT-A plus abnormal vital signs preceding imaging were used to calculate SI, Age SI, National Early Warning Score 2 (NEWS2) and Standardised Early Warning Score (SEWS). A consultant gastrointestinal radiologist further reviewed all consultant-reported scans.ResultsIn total, 930 patients were admitted with LGIB. Median age was 71 years and 51% were male; 179 (19.2%) patients received red blood cell transfusion and 93 patients (10%) underwent CT-A, who were older and were likely to be hypotensive and receive red cell transfusions. Following exclusions, 92 CT-As were included in the analysis. Nine (9.8%) were positive. Univariate analysis showed no association between positive CT-A and any scoring system. A multivariate analysis, including age and gender, showed association between both NEWS2 and SEWS scores with positive CT-A.ConclusionIn our analysis of the typical LGIB population, CT-A has shown relatively low pick up rate of active bleeding. CT-A clearly has a role in the investigation of LGIB, but selection remains challenging.     

Detection of meticillin‐resistant staphylococcus aureus (MRSA) colonization in newborn infants using real‐time polymerase chain reaction (PCR)

Objective: Meticillin‐resistant staphylococcus aureus (MRSA) colonization on neonatal units is a common and important clinical problem. Effectiveness of polymerase chain reaction (PCR) for detecting MRSA nasal colonization of infants was evaluated and compared to culture‐based methods. The effect of skin decolonization in affected infants was studied. Methods: Paired nasal swabs were collected from infants in our neonatal unit over a 12‐month period (September 2007–2008). Colonization with MRSA was determined with a commercially available PCR method and compared to culture. Results: A total of 696 paired nasal swabs were taken. Three infants were colonized at the beginning and were included. There were positive PCRs in 12 infants. Five infants cultured MRSA from a nasal swab at the same time. No infants were culture‐positive when PCR was negative (sensitivity 100%, specificity 99% compared to culture). PCR results were available within 24 h. Five infants were PCR+ and isolated meticillin‐sensitive Staphylococcus aureus. This organism gave a false‐positive PCR result. Two infants transferred in on broad‐spectrum antibiotics were PCR+ and negative by culture. Decolonization led to negative nasal PCR and culture in 4/5 infants to discharge. Conclusions: PCR methods are sensitive and specific for detection of MRSA colonization in newborn infants of all gestations with results 1–2 days before culture.     

Risk management issues related to the use of contrast agents

The authors reviewed retrospectively 2,100 claims filed over an 11-year period in 12 hospitals in a large metropolitan area covered by a single insurance carrier. One hundred cases (5%) involved radiologists, and 10 of these were related to the use of contrast media. Four of the cases reached financial settlement before trial, three were dropped with no financial settlement before tribunal or trial, one was dropped after a tribunal finding for the defendants, and two were decided in favor of the defendants at trial. Multiple issues were raised by the plaintiffs in all 10 cases. The questions of quality of care and of informed consent were raised in 10 and nine cases, respectively. In the four cases that reached a financial settlement, quality of care was thought to be an important issue in three, whereas informed consent was not a key issue in any. Conversely, adequate informed consent was an important consideration in three of the six cases that were dropped. Screening of patients and documentation of risk factors, adverse events, treatment, and follow-up were also important factors in determining outcome. The authors conclude that legal claims relating to use of contrast agents are unusual, most often involve non-life-threatening outcomes, and in most cases do not result in trial or a financial settlement.     

Sensory systems and nipple attachment behavior in neonatal pigs

The influence of piglet sensory systems and the role of odors from the sow's ventrum on piglet nipple attachment were investigated. In Experiment 1, four sows had their ventrum washed with organic solvents and four were unwashed control sows. Piglets were given one of four treatments shortly after birth: nares that were mechanically blocked (B), a lidocaine flush of the olfactory system (LFO), a saline flush of the olfactory system (SFO) or nontreated controls (C). Time to attach to a nipple, up to a maximum of 600 sec, was recorded. On unwashed sows, nipple attachment was affected (p less than 0.01) by piglet treatment. Piglets have B or LFO treatments took longer to attach to a nipple than SFO or C piglets. Piglets of all treatments took longer to attach to washed sows than to unwashed controls. Seven unwashed sows and their litters were used in Experiment 2. Piglets were tested after birth with one of the following treatments: an olfactory system flushed with lidocaine, lidocaine on nose (LN), lidocaine applied to the tongue (LT) or nontreated controls. All lidocaine-treated piglets took more time to attach than C piglets. Nipple attachment latencies were intermediate for LN or LT piglets. In Experiment 3, three unwashed sows and their litters were used. Treatments were: lidocaine applied to both the nose and the tongue (LNT), an olfactory system flushed with lidocaine or nontreated controls. LFO piglets had an increased latency to attachment compared to controls while LNT piglets were intermediate in latency to attach. Piglet olfaction, gustation and tactile sensory modalities as well as odors on the sow's ventrum influenced nipple attachment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anthropometric Studies of Human Subjects Susceptible to Malignant Hyperpyrexia

Height, weight, and skinfold thickness were measured on 82 patients prior to muscle biopsy which was performed to determine their susceptibility to malignant hyperpyrexia. Percentage body fat was calculated from the skinfold measurements. Using AP photographs six coronal diameters of the left thigh. equally spaced between the lower border of the patella and the perineum, were measured on another group of 90 patients referred for biopsy. The subjects were then divided into those who were susceptible to malignant hyperpyrexia (MHS) and those who were normal and acted as controls. Each group was separated into males and females. There was no significant difference in age between the MHS and the control groups. There was no difference between MHS and controls in height or weight but the percentage body fat in the MHS males was significantly lower than in the controls (P<0.02). The upper three thigh diameters in the MHS females were significantly greater than in the control group (P<0.05). There appears to be a difference in the leanness/fatness relationship and in the development of the thigh in MHS subjects compared with controls, but these differences are subtle and appear to vary with sex.