Adenomatous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm

Mutational inactivation of the adenomatous polyposis coli (APC) tumor suppressor initiates most hereditary and sporadic colon carcinomas. Although APC protein is located in both the cytoplasm and the nucleus, the protein domains required to maintain a predominantly cytoplasmic localization are unknown. Here, we demonstrate that nuclear export of APC is mediated by two intrinsic, leucine-rich, nuclear export signals (NESs) located near the amino terminus. Each NES was able to induce the nuclear export of a fused carrier protein. Both APC NESs were independently able to interact with the Crm1 nuclear export factor and substitute for the HIV-1 Rev NES to mediate nuclear mRNA export. Both APC NESs functioned within the context of APC sequence: an amino-terminal APC peptide containing both NESs interacted with Crm1 and showed nuclear export in a heterokaryon nucleocytoplasmic shuttling assay. Also, mutation of both APC NESs resulted in the nuclear accumulation of the full-length, approximately 320-kDa APC protein, further establishing that the two intrinsic APC NESs are necessary for APC protein nuclear export. Moreover, endogenous APC accumulated in the nucleus of cells treated with the Crm1-specific nuclear export inhibitor leptomycin B. Together, these data indicate that APC is a nucleocytoplasmic shuttle protein whose predominantly cytoplasmic localization requires NES function and suggests that APC may be important for signaling between the nuclear and cytoplasmic compartments of epithelial cells.     

Cardiac risk underestimation in urban,black women

BACKGROUND: Black women have a disproportionately higher incidence of cardiovascular disease mortality than other groups and the reason for this health disparity is incompletely understood. Underestimation of personal cardiac risk may play a role. OBJECTIVE: We investigated the personal characteristics associated with underestimating cardiovascular disease in black women. DESIGN, SETTING, PARTICIPANTS: Trained surveyors interviewed 128 black women during the baseline evaluation for a randomized controlled trial in an urban, academic continuity clinic affiliated with a public hospital system. They provided information on the presence of cardiac risk factors and demographic and psychosocial characteristics. These self-report data were supplemented with medical record abstraction for weight. MEASUREMENTS AND MAIN RESULTS: The main outcome measure was the accurate perception of cardiac risk. Objective risk was determined by a simple count of major cardiac risk factors and perceived risk by respondent's answer to a survey question about personal cardiac risk. The burden of cardiac risk factors was high in this population: 77% were obese; 72% had hypertension; 48% had high cholesterol; 49% had a family history of heart disease; 31% had diabetes, and 22% currently used tobacco. Seventy-nine percent had 3 or more cardiac risk factors. Among those with 3 or more risk factors ("high risk"), 63% did not perceive themselves to be at risk for heart disease. Among all patients, objective and perceived cardiac risk was poorly correlated (kappa=0.026). In a multivariable model, increased perceived personal stress and lower income were significant correlates of underestimating cardiac risk. CONCLUSIONS: Urban, disadvantaged black women in this study had many cardiac risk factors, yet routinely underestimated their risk of heart disease. We found that the strongest correlates of underestimation were perceived stress and lower personal income.     

Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ

The application of allogeneic stem cell transplantation (alloSCT) is limited by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic forms that likely have different requirements for initiation and pathogenesis mechanisms. In prior studies we demonstrated that residual host antigen-presenting cells (APCs) were required to initiate acute GVHD (aGVHD) mediated by CD8 T cells. In contrast, here we demonstrate that either donor or host APCs can initiate CD4-mediated GVHD in a model that has features of chronic GVHD (cGVHD). Both donor and host APCs must provide CD80/86-dependent costimulation to elicit maximal cGVHD, and there is no GVHD when both donor and host lack CD80/86. Finally, we were surprised to find that, although either donor or host APCs are sufficient to stimulate skin cGVHD, donor APCs play a dominant role in intestinal cGVHD. Both CD40 and CD80/86 are critical for donor APC function in intestinal cGVHD, but only CD80/86 is required for skin cGVHD. Thus, there are target-tissue-specific differences in APC requirements. These results identify differences in APC requirements between CD8-mediated aGVHD and CD4-mediated cGVHD. They further highlight donor APCs as additional targets for GVHD therapy.     

Contribution to the surgical treatment of patients with cervical spine cord injury using simple procedures

Thirty-nine patients with acute cervical spine fractures and/or dislocations between C3 and C7 were submitted to an anterior approach using bone graft fixation without screw and plate systems and three required a preliminary posterior approach to reduce a dislocation. Graft dislodgement due to technical problems occurred at a rate of 7.7% postoperatively and 2.8% 1 month later. No redislodgement occurred. All fusions became solid after 3 months. Their progress was based on the Frankel scale, before surgery, at the moment of the discharge, and at 6 months follow-up. This experience shows how patients with an acute cervical injury can improve even when admitted late after trauma.     

The validity of self-reported drug use in non-treatment seeking individuals with cocaine dependence: correlation with biochemical assays

Accurate estimate of drug exposure plays an important role in studies of the neurobiology of drug dependence. The validity of self-reported drug use by subjects participating in such studies has not been well established. This study examined the relationship between self-reported drug use and biological markers in 18 non-treatment-seeking cocaine-dependent individuals participating in research on the effects of cocaine on the brain. A significant relationship was found between self-reported frequency of cocaine use and hair cocaine concentration. Frequency of alcohol use correlated significantly with plasma carbohydrate-deficient transferrin and aspartate aminotransferase levels. These results suggest that self-reported substance use in non-treatment seeking research subjects is generally valid.     

Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.     

Hypovitaminosis D: a widespread epidemic

Vitamin D insufficiency is widespread, regardless of geographical location. It is particularly prevalent in the elderly and has far-ranging health consequences including: osteoporosis, falls, increased risk of cancer, and altered glucose and lipid metabolism. Increasing evidence strongly supports the benefits of vitamin D supplementation and also reveals that present recommendations are inadequate, especially for older individuals. Although additional studies are still needed to further optimize diagnostic and therapeutic approaches, physicians should consider prescribing cholecalciferol--at least 2000 international units (IU) per day--to all elderly patients. Oral cholecalciferol supplementation at that level is inexpensive, safe, and effective, and has great potential to improve the quality of life of the elderly.     

The urokinase receptor mediates basic fibroblast growth factor-dependent smooth muscle cell migration through baboon aortic explants

The urokinase receptor is required for vascular smooth muscle cell migration in vitro, but may not be needed in vivo since smooth muscle cell migration and intimal hyperplasia after arterial injury in mice are not affected by urokinase receptor gene deletion. We have used baboon aortic explants as a bridge between cell culture and in vivo experiments to determine if the urokinase receptor is required for smooth muscle cell proliferation and smooth muscle cell migration in primate vessels. Levels of urokinase receptor in explants increased with time after explantation, while blockade of urokinase receptor with an antibody decreased smooth muscle cell proliferation and smooth muscle cell migration from the explants. A blocking antibody to basic fibroblast growth decreased levels of urokinase and urokinase receptor in explants, and it decreased smooth muscle cell migration and mitogenesis. These results suggest that the factor urokinase receptor plays a positive role in smooth muscle cell migration and proliferation in injured primate arterial tissue, in part mediating the pro-migratory and proliferative effects of basic fibroblast growth factor released by damaged smooth muscle cells.