Faculty Bibliography

Evaluation of: Lyytinen H, Pukkala E, Ylikorkala O: Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstet. Gynecol. 108(6), 1354-1360 (2006) [1] . A cohort study of 84,729 Finnish women over the age of 50 years who used oral or transdermal estradiol for at least 6 months, followed for the incidence of breast cancer using a national cancer registry. The study was conducted to evaluate whether the risk of breast cancer with estrogen-only therapy varies by dose, constituents or route of administration. A total of 2171 women developed breast cancer, with no increased risk observed for less than 5 years of use, and some risk for greater than 5 years of use for both oral and transdermal routes of administration

OBJECTIVES: Before the introduction of highly active antiretroviral therapy (HAART), the majority of HIV-infected patients experienced diarrhea. The aims of this study were to compare the prevalence of diarrhea among HIV-infected and uninfected patients in the HAART era, and to evaluate the impact of diarrhea on health-related quality of life (HRQOL). METHODS: Diarrheal symptoms experienced by 163 consecutive HIV-infected patients and 253 HIV-seronegative control subjects were ascertained using a validated questionnaire. The HRQOL of these patients was assessed using the Medical Outcomes Study (MOS) SF-36 and MOS-HIV Health surveys. RESULTS: Among the 163 HIV-infected patients, the median CD4 cell count was 370 cells/mm and 150 individuals were taking HAART. Significantly, more HIV-infected subjects reported having 3 or more bowel movements daily within the past 7 days than did HIV-seronegative subjects (28.2% vs. 7.1%, P<0.001), even after adjusting for potential confounding variables (odds ratios=6.65; 95% confidence intervals, 3.36-13.17). In addition, diarrhea was significantly more common in HIV-infected patients than in control subjects when assessed by several other criteria. HIV-infected patients reported significantly worse HRQOL across all domains of the MOS SF-36 as compared with control subjects. Among HIV-infected patients, individuals with diarrhea had significantly worse HRQOL in nearly all domains of the MOS-HIV as compared with those without diarrhea. CONCLUSIONS: Diarrhea remains an important clinical problem in HIV-infected patients and is associated with significant impairments in HRQOL. It is important that healthcare providers specifically evaluate their HIV-infected patients for diarrhea so that these symptoms may be optimally managed.

During meiosis, double-strand breaks (DSBs) lead to crossovers, thought to arise from the resolution of double Holliday junctions (HJs) by an HJ resolvase. In Schizosaccharomyces pombe, meiotic crossovers are produced primarily through a mechanism requiring the Mus81-Eme1 endonuclease complex. Less is known about the processes that produces crossovers during the repair of DSBs in mitotic cells. We employed an inducible DSB system to determine the role of Rqh1-Top3 and Mus81-Eme1 in mitotic DSB repair and crossover formation in S. pombe. In agreement with the meiotic data, crossovers are suppressed in cells lacking Mus81-Eme1. And relative to the wild type, rqh1Delta cells show a fourfold increase in crossover frequency. This suppression of crossover formation by Rqh1 is dependent on its helicase activity. We found that the synthetic lethality of cells lacking both Rqh1 and Eme1 is suppressed by loss of swi5(+), which allowed us to show that the excess crossovers formed in an rqh1Delta background are independent of Mus81-Eme1. This result suggests that a second process for crossover formation exists in S. pombe and is consistent with our finding that deletion of swi5(+) restored meiotic crossovers in eme1Delta cells. Evidence suggesting that Rqh1 also acts downstream of Swi5 in crossover formation was uncovered in these studies. Our results suggest that during Rhp51-dependent repair of DSBs, Rqh1-Top3 suppresses crossovers in the Rhp57-dependent pathway while Mus81-Eme1 and possibly Rqh1 promote crossovers in the Swi5-dependent pathway.

The objective of this research was to study the factors that relate to the effectiveness of upper-room ultraviolet germicidal irradiation for inactivating airborne microorganisms. The work was conducted in a room-sized chamber designed and furnished for investigations of this nature. Nebulized Serratia marcescens, Bacillus subtilis spores, and vaccinia virus were used as test aerosols. Most data were collected from steady-state experiments comparing the number of viable organisms in the chamber air remaining with UV lamps turned on to the number with UV lamps turned off, but some decay experiments were conducted to compare the two methods. UV power level had a strong influence but was fully effective only in the presence of air mixing that produced vigorous vertical air currents. A conclusion of the study is that an upper-room ultraviolet installation is a complex system that requires careful integration of UV luminaires, UV power, and room ventilation arrangements.

Life-cycle management of drug safety issues requires vigilant postmarket monitoring. Increasingly, however, this concept also includes direct management of how drugs are used, to minimize risks and maximize benefits. Legislative proposals from Senators Kennedy and Enzi, as well as plans offered by the Institute of Medicine, are promoting the more widespread adoption of risk-management plans to mitigate a broader range of safety-related issues. These proposals seek to modify physician prescribing patterns to tip risk-benefit balancing in individual prescription decisions. Yet these policies would do nothing to mitigate the drug safety-related issues that have been the source of recent public interest

BACKGROUND:Methylmalonic acidemia (MMA), a common organic aciduria, is caused by deficiency of the mitochondrial localized, 5'deoxyadenosylcobalamin dependent enzyme, methylmalonyl-CoA mutase (MUT). Liver transplantation in the absence of gross hepatic dysfunction provides supportive therapy and metabolic stability in severely affected patients, which invites the concept of using cell and gene delivery as future treatments for this condition. METHODS:To assess the effectiveness of gene delivery to restore the defective metabolism in this disorder, adenoviral correction experiments were performed using murine Mut embryonic fibroblasts and primary human methylmalonyl-CoA mutase deficient hepatocytes derived from a patient who harbored two early truncating mutations, E224X and R228X, in the MUT gene. Enzymatic and expression studies were used to assess the extent of functional correction. RESULTS:Primary hepatocytes, isolated from the native liver after removal subsequent to a combined liver-kidney transplantation procedure, or Mut murine fibroblasts were infected with a second generation recombinant adenoviral vector that expressed the murine methylmalonyl-CoA mutase as well as eGFP from distinct promoters. After transduction, [1-14C] propionate macromolecular incorporation studies and Western analysis demonstrated complete correction of the enzymatic defect in both cell types. Viral reconstitution of enzymatic expression in the human methylmalonyl-CoA mutase deficient hepatocytes exceeded that seen in fibroblasts or control hepatocytes. CONCLUSION/CONCLUSIONS:These experiments provide proof of principle for viral correction in methylmalonic acidemia and suggest that hepatocyte-directed gene delivery will be an effective therapeutic treatment strategy in both murine models and in human patients. Primary hepatocytes from a liver that was unsuitable for transplantation provided an important resource for these studies.

Tom Shea, the governor's chief of staff, said Mr. [Jon S. Corzine] would not resume his official duties until some time after he is released from the hospital. Richard J. Codey, a fellow Democrat who is president of the State Senate, has been acting governor since the April 12 accident when the Chevrolet Suburban Mr. Corzine was riding in, moving at 91 miles per hour with emergency lights flashing, collided with another car and then slammed into a guardrail on the Garden State Parkway. For now, though, Mr. Corzine cannot even get himself out of bed to sit in a chair, something Dr. [Robert F. Ostrum] said would be a milestone. The doctors said they hoped Mr. Corzine could sit upright for an hour or two later this week. ''That would be a big deal,'' Dr. Ostrum said. Dr. [Steven E. Ross], left, head of trauma, and Tom Shea, Gov. Jon S. Corzine's chief of staff, at Cooper University Hospital in Camden, N.J. (Photo by Tom Mihalek for The New York Times)(pg. B4)