Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.     

Homocysteine and folic acid are inversely related in black women with preeclampsia

Black women have an increased risk of preeclampsia compared with white women. Plasma homocysteine is increased in preeclampsia. Homocysteine concentrations are affected by nutritional deficiencies, particularly decreased folic acid and B12, leading to increased homocysteine. Previous studies have reported racial differences in nutritional intake including folic acid. Therefore, we investigated whether there were racial differences in plasma homocysteine, folic acid, and vitamin B12 among women with preeclampsia. We tested for an association between homocysteine and folic acid and B12, and we hypothesized an inverse relationship of homocysteine and folic acid in preeclampsia, more so in black women in whom preeclampsia developed. Black women with preeclampsia (n=26) had elevated homocysteine concentrations (8.7+/-1.4 micromol/L) compared with black women with normal pregnancy (n=52, 7.6+/-0.5 micromol/L), white women with preeclampsia (n=34, 7.5+/-0.6 micromol/L), and white women with normal pregnancy (n=48, 5.5+/-0.3 micromol/L). Folic acid concentrations were lower in black women (14.1+/-0.8 ng/mL) compared with white women (18.5+/-0.9 ng/mL, P<0.01). However, plasma homocysteine was inversely related to folic acid only among black women with preeclampsia (r=-0.23, P=0.01). These racial differences may have implications for the higher rates of preeclampsia in this group and may have long-term implications for future cardiovascular risk. Racial differences in diet, adherence to folic acid supplementation, or interactions of nutritional and maternal factors warrant further study by race and pregnancy status.     

Analysis of factors contributing to long-term success among graduates of aresidential weight management program for women

This study evaluated several components of a residential weight loss program for adult women and compared the characteristics of successful and nonsuccessful participants. Program components included a 1000–1200-kcal daily diet, nutrition counseling, behavior modification, and regular exercise. Weight loss averaged 7 kg during an average 35-day stay. Thirty-eight percent of participants (n = 226) responded to questionnaires that were mailed 6 months to 5 years after participation. Respondents did not differ on any baseline measure of body composition or characteristics from nonrespondents including degree of overweight, rate of weight loss, etc. Nineteen percent reported weight increment since initial attendance. Fifty-two percent of the respondents reported maintenance of all weight loss with 18% losing an additional 5 kg and 8% losing an additional 9 kg. Duration of time since attendance and repeated visits were not related to successful weight maintenance. No behavioral profile discriminated between successful and unsuccessful respondents. However, continued success was related to increased and regular exercise and later age of onset of obesity.     

CCK as a modulator of cardiovascular function

The gut-brain peptide cholecystokinin (CCK) has been implicated in a wide range of physiological processes including digestion, satiety, anxiety, nociception and lordosis. In addition, it is becoming clear that CCK is involved in regulating certain aspects of cardiovascular function. This article reviews the cardiovascular effects elicited by CCK via its actions at both central and peripheral sites and considers the physiological role of the peptide with respect to the cardiovascular function in different physiological and pathophysiological states. In the periphery CCK released from entoeroendocrine cells in the gut wall in response to a meal triggers a local postprandial hyperaemia in the gut that could promote digestion by facilitating intestinal motility and secretory processes. In addition, activation of CCK receptors on abdominal vagal afferents elicits a reflexly evoked hyperaemia that potentiates these effects and is also gasroprotective. In the brain CCK appears to act as a neuromodulator rather than a direct mediator within cardiovascular control circuits. In particular, it facilitates activity in amygdalar, hypothalamic and midbrain circuits that are involved in mediating acute cardiovascular and behavioural responses to an extreme physical or psychologically stressful challenge. Whilst in the short term activation of the CCK system appears to be beneficial to the organism, chronic stimulation of the system may be maladaptive, laying the foundation for the development of pathophysiological conditions such as panic disorder and chronic pain, both of which are states characterised by significant autonomic activation.     

Changes in the pathogenicity of relapsed diminazene aceturate (DA)-resistant Trypanosoma brucei brucei as the trypanosomes are transmitted from DA-treated hosts to another set of animals

This study investigated the changes in pathogenicity of relapsed diminazene aceturate (DA)-resistant Trypanosoma brucei brucei (TBB) as the trypanosomes are transmitted from DA-treated hosts to another set of animals. The Federe strain of T. brucei brucei which was known to be DA resistant was used to infect two groups of rats, one of which was treated at the peak of infection. There was temporary clearance of the trypanosomes from blood of the treated group and subsequent relapse of the infection. The relapsed trypanosomes were used to infect a group of rats (group A1), and the pathogenicity of the relapsed T. brucei brucei in this rat group was compared to that of a group infected with primary T. brucei brucei stock that was not treated with DA (group B1). Results showed that when compared with the B1 rats, the A1 group had a slower onset of parasitaemia, significantly lower (p < 0.01) level of parasitaemia all through the study, significantly longer (p < 0.01) time period to reach peak parasitaemia, significantly longer (p < 0.01) post-infection survival time and significantly higher (p < 0.05) packed cell volume from day 6 post-infection. Further sequential transmission of this same T. brucei brucei infection to another group of rats (A2 and B2) produced the same effects on the above parameters used to assess pathogenicity. It was concluded that beyond temporarily clearing trypanosomes from blood of treated animals, treatment with DA reduces the pathogenicity of DA-resistant T. brucei brucei, and this reduced pathogenicity is carried on as the T. brucei brucei is further sequentially transmitted to another set of animals.     

Positive Impact of a Shelter-based Hepatitis B Vaccine Program in Homeless Baltimore Children and Adolescents

Homeless youth are at increased risk for hepatitis B virus (HBV) infection and HBV vaccine coverage is poor in this group. The purpose of our study was to determine if a shelter-based HBV vaccine program in children and adolescents 2–18 years of age with a randomized controlled trial using a culturally appropriate HBV video could increase HBV vaccine coverage rates. Subjects were randomized to an 8 min HBV video or a control, smoking prevention video. Before exposure to the videos, HBV knowledge, and demographics were assessed in caregivers and adolescents. HBV vaccine no. 1 was offered to all subjects who did not produce a vaccine record; subsequently, an accurate HBV vaccine history was obtained from medical providers. Subjects were asked to return 1 and 3 months after visit 1, HBV vaccine was offered to all with incomplete coverage, and HBV knowledge was reassessed. There were 328 children and adolescents cared for by 170 caregivers enrolled in the study. One hundred and four had incomplete HBV vaccine coverage. Data are reported for all family units with at least one subject needing vaccine. There were 53 children and adolescents randomized to the HBV video vs. 51 to the smoking video. HBV knowledge scores of caregivers improved at Visit no. 2 vs. no. 1 in the HBV video group (p = 0.01) but not in the smoking group (p = 0.82). Similar results were observed for adolescents in the HBV video group (p = 0.05) but not in the smoking group (p = 0.40). Exposure to the HBV video vs the smoking video had a significant effect on return rates for vaccine at Visit no. 2 (59 vs. 31%; p = 0.05) but not at Visit no. 3 (47 vs. 18%, p = 0.06). The shelter-based vaccine program was very effective in increasing HBV coverage rates in the entire group of 328 children and adolescents enrolled in the study, from 68% coverage at baseline to 85% at the conclusion of the study. We conclude that shelter-based HBV vaccine programs can be highly effective in increasing vaccine coverage rates in older children and adolescents. A brief exposure to a culturally appropriate HBV video improves HBV knowledge and may improve return rates for vaccine.     

Family medicine month in a university-based program: establishing a family medicine identity

"Family Medicine Month," a rotation forfirst-year residents, was developed to clarifyfirst-year residents'new roles as family physicians. The rotation explored the meaning and history of the specialty, as well as teaching core family medicine clinical and behavioral skills. Twenty residents who participated in the rotation in 1999 and 2000 indicated satisfaction with the rotation and endorsed its usefulness. They also reported greater self efficacy in performing family practice skills after the rotation, compared with before the rotation. Results suggest that a curriculum based on the context of family medicine as a specialty enhances resident satisfaction and self efficacy.