Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy.

Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer.

Bisphenol A affects larval growth and advances the onset of metamorphosis in Drosophila melanogaster.

Exposure to Bisphenol A (BPA) has been reported to dysregulate endocrine pathways in a wide array of vertebrate species. The effects of BPA on invertebrate species are less well understood. We tested the effects of BPA on growth and development in Drosophila as these processes are governed by well-studied endocrine pathways. In this study, we tested the effects of three concentrations of BPA (0.1mg/L, 1mg/L or 10mg/L) and found a statistically significant increase in larval growth for the low dose treatment group (0.1mg/L), but not statistically significant for the high dose treatment group (10mg/L). BPA exposure resulted in an increased body size in treated animals at 48, 72 and 96h after egg laying (AEL). This finding reflects a non-monotonic dose-response that has been observed for an increasing number of endocrine disrupting compounds. The increase in growth rate found for all treatment groups was associated with a statistically significant increase in food intake observed at 72h AEL. Furthermore, we observed that the increased growth rate was coupled with an earlier onset of pupariation consistent with previously reported phenotypes resulting from increased activity of insulin/insulin growth factor signaling (IIS) in Drosophila. Since the timing of the onset of pupariation in Drosophila is controlled through the complex interaction of the IIS and the ecdysone signaling pathways, our findings suggest that BPA exerts its effects through disruption of endocrine signaling in Drosophila.

Pseudotyping the adenovirus serotype 5 capsid with both the fibre and penton of serotype 35 enhances vascular smooth muscle cell transduction.

Ex vivo gene therapy during coronary artery bypass grafting (CABG) holds great potential to prevent excessive smooth muscle cell (SMC) proliferation, neointima formation and graft failure. The most successful preclinical strategies to date have utilised vectors based on the species C adenovirus, Ad5, which engages the Coxsackie and Adenovirus receptor (CAR) as its primary attachment receptor. Profiling receptors on human SMCs demonstrated the absence of CAR but substantial expression of the species B receptor CD46. We performed transduction experiments using Ad5 and the CD46-utilising adenovirus Ad35, and found Ad35 significantly more efficient at transducing SMCs. To evaluate whether transduction could be further augmented, we evaluated chimeric CD46-utilising Ad5/Ad35 vectors comprising the Ad5 capsid pseudotyped with the Ad35 fibre alone (Ad5/F35) or in combination with the Ad35 penton (Ad5/F35/P35). In human smooth muscle cells (hSMCs), Ad5/F35/P35 mediated significantly higher levels of transduction than either parental vector or Ad5/F35. Ex vivo transduction experiments using mouse aortas from CD46 transgenics demonstrated that Ad5/F35/P35 was significantly more efficient at transducing SMCs than the other vectors tested. Finally, ex vivo transduction and immunofluorescent colocalisation experiments using human tissue from CABG procedures confirmed the preclinical potential of Ad5/F35/P35 as an efficient vector for vascular transduction during CABG.

Accidents and injuries among U.S. Navy crewmembers during extended submarine patrols, 1997 to 1999.

Accidents and injuries, the most common cause of morbidity in military populations, result in a significant number of work days lost each year and account for 75% of all active duty deaths. Rates of accidents and injuries during U.S. Navy submarine deployments have not been evaluated previously. A database designed to monitor the health of submarine crew-members was used to examine the rates and causes of accidents among deployed crewmembers aboard 196 submarine patrols between 1997 and mid 1999. The most common category of injuries was open wounds, followed by sprains and strains, contusions, superficial injuries, burns, and others. Rates of accidents and injuries decreased with increasing age and duration of military service. Among submariners working in supply departments, the rates were more than two times those of crewmembers working in other departments. Based on these data, among a submarine crew of 100 men at sea for 100 days, approximately four to five accidents or injuries might be expected and would result in an average of about 2 days of light or no duty per injury. Rates of accidents and injuries were very low; however, focused safety training could reduce rates among younger and less experienced crewmembers as well as among those working in particular areas of the submarine.

Factors affecting college students' perceptions of sexual relationships between high school students and teachers.

This study explored the effects of respondent gender, gender combination (male teacher/female student versus female teacher/male student), and teacher age (24 versus 39-years-old) on the perception of a sexual relationship between a teacher and a 16-year-old student. Participants were 80 male and 80 female undergraduates. A MANOVA yielded significant main effects for respondent gender and gender combination. Subsequent ANOVAs indicated that men generally viewed the experience more positively and that the male teacher/female student combination was viewed more negatively than the female teacher/male student pairing.

Effect of dietary vitamin E supplementation on the integrity of skeletal muscle in exercised horses.

The effect of vitamin E intake on indicators of muscle integrity was studied in exercised horses. Nineteen horses were blocked by sex and then assigned to one of three diets: no supplemental vitamin E (BASAL), BASAL plus 80 IU of supplemental vitamin E/kg DM (80), or BASAL plus 300 IU of supplemental vitamin E/kg DM (300). The BASAL diet contained less than 44 IU of vitamin E/kg DM, but it was adequate in all other nutrients. During the 90-d treatment period, horses were exercised 5 d/wk; in addition, serum and middle gluteal muscle alpha-tocopherol concentrations were measured at 0, 30, and 90 d. All horses performed a repeated submaximal exercise test (RSET) at the end of the 90-d period. The following were measured before and after the RSET: alpha-tocopherol, thiobarbituric acid reactive substances (TBARS), conjugated diene (CD) concentrations of the middle gluteal muscle, and serum creatine kinase (CK) and aspartate aminotransferase (AST) activities. Serum alpha-tocopherol concentrations of horses receiving the BASAL and 80 diets decreased (P < .05 and P < .06, respectively) during the 90-d treatment period but did not change in horses receiving the 300 diet. Serum and muscle alpha-tocopherol concentrations were higher (P < .05) at 30 and 90 d in horses receiving the 300 diet than in horses receiving the BASAL and 80 diets. Serum CK and AST activities increased (P < .05) following RSET but were not affected by dietary vitamin E level. Muscle alpha-tocopherol level did not affect muscle CD or TBARS.

Mechanism of ATP-induced leukocyte adherence to cultured pulmonary artery endothelial cells.

Previously we have shown that ATP enhances the adherence of HL-60 cells and human neutrophils to bovine pulmonary artery endothelial cells. The current investigations extend earlier findings by showing that ATP and UTP dose-dependently stimulate human neutrophil adherence to human pulmonary artery endothelial cells. We have also explore the mechanisms of ATP- and UTP-stimulated adherence. We have found that fucose, a component of selectin receptors, inhibits ATP-stimulated HL-60 cell-bovine pulmonary artery endothelial cell adhesion. Additionally, pretreatment of HL-60 cells with neuraminidase abolishes ATP enhancement. However, fucose does not affect ATP- or thrombin-induced adhesion of freshly isolated human neutrophils to human endothelial cells. Antibodies to human P-selection intercellular adhesion molecule (ICAM)-1, and the beta-subunit of CD11/CD18 do not alter ATP-induced adherence of HL-60 cells to bovine endothelial cells. Similarly, antibodies to human P-selectin and ICAM-1 do not inhibit human neutrophil-human pulmonary artery endothelial cell adhesion. The platelet-activating factor receptor antagonists, WEB-2086 and L-659,989, are effective in attenuating ATP- and UTP-stimulated adherence. Preincubation of neutrophils or human pulmonary artery endothelial cells with ATP or UTP also enhances adherence, an effect that is blocked by L-659,989. Thus platelet activating factor, associated with both neutrophils and endothelial cells, mediates ATP- and UTP-induced neutrophil adherence. ATP, released during vascular injury, may exacerbate neutrophil-endothelial cell interaction and thereby contribute to neutrophil-induced injury.

The effect of edge orientation and movement direction on the apparent misalignment of collinear bars.

Four experiments on apparent misalignment of oblique collinear bars are reported. The data from the first three experiments showed that the misalignment was slight but significant when no direction other than that of the bars themselves was delineated and about double when the vertical was delineated by movements of the adjustable bar. When the vertical was delineated by both these movements and the ends of the bars (or by vertical parallel lines), the misalignment was more than six times greater. Conversely, it was reduced when the bar ends delineated the vertical and bar movements delineated the direction at right angles to the bars. The data from a fourth experiment showed that the inner pair of edges were closely involved in apparent misalignment and that the outer ends were not. The relationship between the misalignment effect with bars and the Poggendorff figure (oblique lines separated by parallels), the delineation of direction by edges and movement, and the implications of these data for an explanation are discussed.

Disappearance of duodenal polyps in Gardner's syndrome with sulindac therapy.

Duodenal polyps with a malignant potential pose a serious threat to Gardner's patients. Several reports have shown regression or disappearance of colonic polyps with sulindac therapy. We report the first case of disappearance of duodenal polyps with sulindac.

Pregnancy-related mortality in New Jersey, 1975 to 1989.

OBJECTIVES: National data are thought to underestimate pregnancy-related mortality in the United States. A multisource surveillance system for pregnancy-associated deaths in New Jersey offers an opportunity to identify the magnitude of and the trends in pregnancy-related mortality at the state level. METHODS: Data from all reported pregnancy-related deaths in the state from 1975 to 1989 were studied, and pregnancy mortality ratios were calculated. RESULTS: The New Jersey pregnancy mortality ratio decreased from the late 1970s to the early 1980s but began to rise in the late 1980s. The pregnancy mortality ratio for non-Whites was 3.6 times that for Whites for the 15-year period. The causes of pregnancy-related deaths changed over the 15-year period, with direct obstetrical causes playing a decreasing role. AIDS has become the major cause of pregnancy-related mortality in New Jersey. Finally, approximately 44% of the pregnancy-related deaths were considered to be preventable by the physician or patient or both. CONCLUSIONS: New efforts must be made to combat the recent rise in pregnancy-related deaths, with special attention to preventing deaths among non-White women.

The Poggendorff illusion and apparent interparallel extents.

An explanation of the Poggendorff misalignment effect in terms of apparent contraction of interparallel extent resulting from the Müller-Lyer illusion was tested in three experiments. Three of the eight stimulus figures had oblique transversals outside the parallels in the usual way, three had them inside, and two were controls consisting of the transversals only. Müller-Lyer forms were differently delineated between the parallels for the inside-transversal and outside-transversal figures, and were not delineated in the control figures. In the first experiment apparent misalignment occurred in four of the six parallel-line figures and in neither of the controls. In the second experiment oblique extent between the parallels was underestimated in six of the eight figures and right-angle extent was overestimated in all of them. The results of the third experiment showed that right-angle (horizontal) extent between the parallels without transversals is estimated without significant error. The data from the three experiments do not support the interparallel-extent explanation of apparent misalignment. Instead, the results are interpreted in terms of independent perceptual compromises, one involving alignment of the transversals and the other the distance between them.

Pregnancy-associated deaths due to AIDS in the United States.

From 1981 to 1988, eighty percent of all women with the acquired immunodeficiency syndrome (AIDS) reported to the Centers for Disease Control were of reproductive age. Six pregnancy-associated deaths due to AIDS in this country have been reported in the medical literature. We identified 20 unpublished cases of women who died of AIDS during or within one year after termination of pregnancy. Analysis showed that these women were mostly black or Hispanic, half were intravenous drug abusers, and most died of Pneumocystis carinii pneumonia. Each pregnancy had an obstetric complication, primarily preterm delivery. The interval between diagnosis of AIDS and the death of these women ranged from one day to 15 months, with a mean interval of 113 days. Multiple reporting sources increased case detection and should be used for future investigations. Prospective case-control studies are needed to determine any further relationship between pregnancy complications and AIDS.

Gastrointestinal dissemination of coccidioidomycosis.

An unusual case of extensive gastrointestinal involvement by the fungus Coccidioides immitis is reported in a 21-yr-old man. This unique case demonstrates the occurrence of this fungus within chylous ascites, the mesentery, and invasion of the entire length of the small bowel. Histological and cultural documentation for gastrointestinal tract involvement by C. immitis other than for the rare occurrence of peritonitis has not been previously reported. The significance of the disseminated gastrointestinal coccidioidomycosis in the setting of chylous ascites and extensive abdominal lymphatic involvement is discussed with respect to its pathogenesis and treatment.

Pectus excavatum defect on liver-spleen scintigraphy.

A 58-year-old man with a pectus excavatum demonstrated a photon-deficient defect within the left lobe of the liver on liver-spleen scintigraphy using Tc-99m SCOL. Computed tomography of the liver clearly revealed the abnormal defect seen on the liver-spleen scan to be due to the pectus excavatum. This case confirms the impression that these skeletal aberrations may cause false-positive hepatic defects.

Combined common bile duct and gastric outlet obstruction demonstrated during hepatobiliary scintigraphy.

A 64-year-old man presented with jaundice. Hepatobiliary imaging using 99mTc-DISIDA revealed complete hepatobiliary tract obstruction with a photopenic area corresponding to a dilated gallbladder and a large photopenic region corresponding to a distended stomach as a result of gastric outlet obstruction. At surgery, carcinoma of the head of the pancreas was found to be the cause of the combined common bile duct and gastric outlet obstruction.

Scintigraphic and radiographic findings in Caroli's disease.

In recent years, noninvasive evaluation of Caroli's disease has been demonstrated by computed tomography, ultrasonography, and nuclear scintigraphy. Confirmation of Caroli's disease requires invasive procedures such as percutaneous transhepatic cholangiography or endoscopic retrograde cholangiography. All of the techniques give valuable information making it easier to diagnose Caroli's disease and to determine its extent. In addition, associated abnormalities in organs outside of the biliary system may be revealed. Two cases are presented to illustrate the radiographic and scintigraphic findings of Caroli's disease.