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Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.

We show that the statistical properties of a vibrated granular bead chain are similar to standard models of polymers in equilibrium. Granular chains of length up to N=1024 beads were confined within a circular vibrating bed, and their configurations were imaged. To differentiate the effects of persistence and confinement on the chain, we compared with simulations of both persistent random-walk (RW) and self-avoiding walk (SAW) models. Static properties, such as the radius of gyration and structure factor, are governed for short chains (N

Do preschool children appreciate numerical value as an abstract property of a set of objects? We tested the influence of stimulus features such as size, shape, and color on preschool children's developing nonverbal numerical abilities. Children between 3 and 5 years of age were tested on their ability to estimate number when the sizes, shapes, and colors of the elements in an array were varied (heterogeneous condition) versus when they did not vary (homogeneous condition). One group of children was tested on an ordinal task in which the goal was to select the smaller of two arrays while another group of children was tested on a match-to-sample task in which the goal was to choose one of two visual arrays that matched the sample in number. Children performed above chance on both homogeneous and heterogeneous stimuli in both tasks. However, while children showed no impairment on heterogeneous relative to homogeneous arrays in the ordering task, performance was impaired by heterogeneity in the matching task. We suggest that nonverbal numerical abstraction occurs early in development, but specific task objectives may prevent children from engaging in numerical abstraction.

Purpose: The aim of this study was to determine the incidence, risk factors, and proper management for asymptomatic cholelithiasis in children undergoing bone marrow transplantation (BMT)., Methods: The authors reviewed retrospectively the records of 575 children who underwent bone marrow transplantation at a University bone marrow transplantation unit (BMT) unit between February 1991 and October 1999. Of these patients, 235 underwent abdominal ultrasonography for evaluation of jaundice, sepsis, abdominal pain, or metastasis. To identify risk factors for cholelithiasis, the authors stratified the patients based on their disease and treatment regimen. Finally, the authors analyzed the natural history and management of BMT children with cholelithiasis., Results: The authors identified 20 cases of cholelithiasis (8.5%) in the 235 BMT patients who underwent ultrasonography. Children who underwent BMT to treat bone marrow failure showed a significantly increased risk of cholelithiasis compared with children treated for malignancy (27% v 7.4%; P<.01). Most children (85%) with gallstones did not require surgical intervention. Specifically, 9 (45%) died from their primary disease, 5 (25%) showed sonographic resolution of their gallstones, and 3 (15%) underwent follow-up nonoperatively with persistent cholelithiasis. Three of the 20 patients with gallstones (15%) had signs of acute cholecystitis and underwent surgery. There were no surgical complications or deaths in the operative group., Conclusions: Cholelithiasis occurs at a high incidence in pediatric bone marrow transplant patients. Children undergoing BMT for bone marrow failure are at higher risk of having gallstones than those being treated for malignancy. Finally, these data support a strategy of nonoperative management for asymptomatic cholelithiasis in this highly selected group of patients.

Objective: Our purpose was to compare the efficacy and safety of misoprostol with dinoprostone (Prepidil) for labor induction., Study Design: In a randomized, controlled trial of labor induction, patients were randomly assigned to receive either 50 microgram of intravaginal misoprostol every 4 hours or 0.5 mg of intracervical prostaglandin E2 every 6 hours. Eligibility criteria included gestation of >/=31 weeks, Bishop score <6, and fewer than 12 contractions per hour. Primary outcomes were cesarean section, induction to delivery time, oxytocin use, and fetal distress requiring delivery., Results: One hundred fifty-nine women were randomly assigned to receive misoprostol (n = 81) or Prepidil (n = 78). There were no differences in the indication for induction, preinduction Bishop score, epidural use, or cesarean section rate. Mean time to delivery was significantly shorter in the misoprostol group (19 hours 50 minutes) than in the Prepidil group (28 hours 52 minutes) (P =.005). Only 58% of women in the misoprostol group required oxytocin augmentation, in comparison with 88% of women receiving Prepidil (P =.00002). However, 41% of women receiving misoprostol and 17% receiving Prepidil had late decelerations or bradycardias (P =.001), and 20% of the misoprostol group and 5% of the Prepidil group had deliveries for fetal distress (P =.05)., Conclusions: Misoprostol is more efficacious than Prepidil for labor induction. However, the significantly increased incidence of abnormal fetal heart rate tracings and the trend in increased deliveries for fetal distress with misoprostol dosing of 50 microgram every 4 hours are of concern. These data suggest that either a lower dose of misoprostol or less frequent dosing of misoprostol should be considered.

Objective: To determine whether repeat external cephalic version subsequent to initial failed version resulted in a decreased cesarean section rate and hospital cost., Study Design: All women who underwent repeat external cephalic version after initial failed version were identified and their charts reviewed. Data collected included success of version, mode of delivery, presentation in labor, hospital days, hospital cost, parity and birth weight., Results: Thirty-six women had a repeat external cephalic version attempt from 1987 to 1992. Six, or 17%, of these were successful. All the successful versions were vertex in labor and had a vaginal delivery. Only 6, or 21%, of the failed versions had a vaginal delivery (P < or = .0002). The mean hospital stay was 2.0 and 3.0 days in the successful and failed groups, respectively. The mean hospital cost, expressed in 1992 dollars, was significantly greater in the failed group: $8,042 vs. $5,059 (P < or = .03)., Conclusion: Repeat version was associated with a decrease in the cesarean section rate and hospital cost and should be considered in the management of nonvertex term presentations.

Objective: To test the hypothesis that maternal oral hydration would increase the amniotic fluid (AF) index in pregnancies with normal AF., Methods: Forty women with a normal AF index (7.0-24.0 cm) were randomized to either the control or hydration group. Women in the hydration group drank 2 L of water and returned for the post-treatment AF index in 4-6 hours, whereas women in the control group drank only 100 mL of water during the same time period. The investigator performing the AF index was blinded to the subject's group. The pre- and post-treatment AF indexes and maternal urine specific gravities were compared between the groups., Results: The mean AF index in the hydration group increased significantly by 3.0 +/- 2.4 cm (P < or = .0001) whereas it declined significantly by 1.5 +/- 2.7 cm in the control group (P < or = .02). The maternal urine specific gravities also changed significantly in the expected direction, with those in the hydration group decreasing and those in the control group increasing (P < or = .0001). There was a regression coefficient of -0.6 (P < or = .0001) between the change in urine specific gravity and the change in AF index. The mean time between the pre- and post-treatment AF indexes was not different between the groups., Conclusions: Maternal oral hydration increased the AF index by approximately 16%, whereas fluid restriction decreased the AF index by 8% in women with normal AF. These findings support previous data that maternal hydration increased the AF index by 31% in women with decreased AF and suggest that maternal fluid volume or osmolality may have a role in maintaining the AF volume.

Although adequate amniotic fluid (AF) volume is considered an important aspect of fetal well-being, the etiology of decreased AF volume is not well understood. A randomized blinded trial was designed to examine our hypothesis that maternal hydration would increase the AF index in women with low AF indexes. Women seen in our testing centers were randomized into control or hydration groups. The control group was instructed to drink their normal amount of fluid; the hydration group was instructed to drink 2 L of water, in addition to their usual amount of fluid, 2-4 hours before the post-treatment AF index. The women returned for the post-treatment AF index the same or following day. The mean post-treatment AF index was significantly greater in the hydration group (6.3 versus 5.1; P less than .01), as was the mean change in AF index (post-treatment AF index--pre-treatment AF index: 1.5 versus 0.31; P less than .01). These findings suggest that maternal oral hydration increases AF volume in women with decreased fluid levels.

Brooke Army Medical Center Tumor Registry records from 1947 through 1980 were reviewed. One hundred forty of 819 patients with colorectal cancer were aged 40 or less. The 5 year survival rate was 35 percent and the 10 year survival rate 32 percent. The predominant presenting symptoms were bleeding, pain and change of bowel habits. The median duration of symptoms was 3 months. There were no Dukes'A patients. The 5 and 10 year survival rates in 19 Dukes' B patients were 67 percent. Thirty-three Dukes' C patients had 5 and 10 year survival rates of 37 and 30 percent, respectively. In 42 Dukes' D patients, however, there were no 5 year survivors, and the mean length of survival was only 10 months. Our findings support previous surveys which have concluded that stage at the time of diagnosis, rather than symptoms, duration or patient age, is the most accurate prognostic factor.