Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years.

BACKGROUND AND OBJECTIVES: Neurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking-Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function-Preschool Version and subscales and other indexes of both measures. RESULTS: The primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD. DISCUSSION: Our findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], p = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], p = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], p = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], p = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose. TRIAL REGISTRATION INFORMATION: The study is registered at ClinicalTrials.gov as NCT01730170.

IL-1B(3954) polymorphism and red complex bacteria increase IL-1ß (GCF) levels in periodontitis.

OBJECTIVE: The aim of this study was to compare IL-1ß levels in gingival crevicular fluid (GCF) from healthy and periodontitis sites of IL-1B(3954)-Single Nucleotide Polymorphism (SNP) positive and IL-1B(3954)-SNP negative periodontitis subjects in association with their bacterial profiles. BACKGROUND: Susceptibility to periodontitis has been associated with several risk factors, including allelic variants at multiple gene loci. Variations in the IL-1 gene cluster have been linked with increased risk for periodontitis. IL-1B(3954)-SNP has been previously associated with increased levels of IL-1ß in GCF or periodontal tissues in chronic periodontitis patients, as well as higher levels of specific periodontal pathogens. There is insufficient evidence to conclude if IL-1B gene polymorphisms affect the susceptibility to periodontitis by ultimately modulating the levels of IL-1ß in GCF, the subgingival microbial profile or both. MATERIALS AND METHODS: GCF, subgingival plaque, and buccal epithelial cells were collected from 32 individuals with periodontitis. GCF IL-1ß levels were measured by an enzyme-linked immunosorbent assay (ELISA). Bacterial plaque samples were analyzed for 11 periodontal pathogens using polymerase chain reaction (PCR) analysis with specific primers for the 16SrRNA gene of each bacterium. IL-1B(3954)-SNP status was determined by identifying the carriers of the polymorphic T allele. RESULTS: A significant association was shown between IL-1B(3954)-SNP and IL-1ß GCF levels (amount and concentration). The concomitant presence of two or three red complex bacterial species was associated with increased IL-1ß GCF levels in periodontitis sites (site-level analysis). The concurrent presence of all three red complex periodontal pathogens and IL-1B(3954)-SNP was associated with the highest IL-1ß GCF levels in periodontitis sites. CONCLUSIONS: Our results indicate an independent association of both IL-1B(3954)-SNP and red complex bacterial species with increased IL-1ß levels in GCF of periodontitis sites. A better understanding of the interaction between genetics, bacteria, and inflammation is essential to develop more effective diagnostic, prognostic, and therapeutic tools for periodontitis.

Assessing recovery rate methods: A review and application for human skeletal assemblages.

OBJECTIVES: Recovery rates reflect the amount of recovered skeletal materials based on expectations about the total number of elements or individuals that should be present in an assemblage. It is an underlying concept that reflects analytical potential, wherein high recovery rates typically indicate high analytical capabilities. However, numerous methods are available to calculate different types of recovery rates, and each method addresses various types of research questions and utilizes different variables. Therefore, recovery rates cannot be applied and compared directly, and the appropriate recovery rate for any given research question must be considered thoughtfully. MATERIALS AND METHODS: Several methods of determining individual and element recovery rates are applied to the USS Oklahoma commingled human remains assemblage and discussed with regard to their utility. RESULTS: Depending on which method is used, recovery rates range from 91 to 102% for the recovery of individuals and 0.02 to 91% for the recovery of elements within this assemblage. DISCUSSION: These results emphasize the need to carefully consider which recovery rate is most appropriate based on associated research questions and project contexts. We introduce the idea of the analytical recovery rate, a flexible concept to determine the potential assessment of biological profile parameters once individuation of commingled remains has occurred, wherein elements are selected based on the needs of the project as well as element preservation.

Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.

OBJECTIVE: Emerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. METHODS: The NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age). RESULTS: Periconceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function-Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age. CONCLUSIONS: Use of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development. CLINICALTRIALSGOV IDENTIFIER: NCT00021866.

Association of Varus Knee Thrust During Walking With Worsening Western Ontario and McMaster Universities Osteoarthritis Index Knee Pain: A Prospective Cohort Study.

OBJECTIVE: To investigate the 2-year association of varus knee thrust observed during walking to the odds of worsening Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain in older adults with or at risk of osteoarthritis (OA). METHODS: Video recordings of self-paced walking trials of Multicenter Osteoarthritis Study participants were assessed for the presence of varus thrust at baseline. Knee pain was assessed using the WOMAC questionnaire at baseline and at 2 years. Logistic regression was used to estimate the odds of worsening knee pain (defined as either any increase in WOMAC score or as clinically important worsening), adjusting for age, sex, race, body mass index, clinic site, gait speed, and static knee alignment. Analyses were repeated, stratified by baseline radiographic OA status and among the subset of knees without baseline WOMAC pain. RESULTS: A total of 1,623 participants contributed 3,204 knees. Varus thrust was observed in 31.5% of knees. Knees with varus thrust had 1.44 times (95% confidence interval [95% CI] 1.19-1.73) the odds of any worsening and 1.37 times (95% CI 1.11-1.69) the odds of clinically important worsening WOMAC pain compared to knees without thrust. Knees with thrust without baseline WOMAC pain had 2.01 times (95% CI 1.47-2.74) the odds of incident total pain. CONCLUSION: Results indicate that varus thrust is a risk factor for worsening and incident knee pain. Targeting varus thrust through noninvasive therapies could prevent development or worsening of knee pain in older adults with or at risk for knee OA.

Cost Drivers of a Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Phase 3 Clinical Trial.

Background: Studies indicate that the prevalence of multidrug-resistant infections, including hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), has been rising. There are many challenges associated with these disease conditions and the ability to develop new treatments. Additionally, HABP/VABP clinical trials are very costly to conduct given their complex protocol designs and the difficulty in recruiting and retaining patients. Methods: With input from clinicians, representatives from industry, and the US Food and Drug Administration, we conducted a study to (1) evaluate the drivers of HABP/VABP phase 3 direct and indirect clinical trial costs; (2) to identify opportunities to lower these costs; and (3) to compare (1) and (2) to endocrine and oncology clinical trials. Benchmark data were gathered from proprietary and commercial databases and used to create a model that calculates the fully loaded (direct and indirect) cost of typical phase 3 HABP/VABP endocrine and oncology clinical trials. Results: Results indicate that the cost per patient for a 200-site, 1000-patient phase 3 HABP/VABP study is $89600 per patient. The cost of screen failures and screen failure rates are the main cost drivers. Conclusions: Results indicate that biopharmaceutical companies and regulatory agencies should consider strategies to improve screening and recruitment to decrease HABP/VABP clinical trial costs.

Prevalence of Metabolic Syndrome and Its Individual Components Among Midwestern University Students.

Michigan has the 17th highest adult obesity rate in the United States. Among college-aged adults between 18 and 25 years old, the rate of obesity was 11.6%. Obesity is a key precedent for the development of metabolic syndrome. Accordingly, the purpose of this study was to examine the prevalence of metabolic syndrome and its individual components among a sample of students at Central Michigan University. A cross-sectional survey was conducted among 462 students, aged 18-25 years, in Spring 2015 and Fall/Spring 2016 semesters. Students were recruited throughout the campus via flyers, in-class, and Blackboard announcements. Biochemical, anthropometric, and blood pressure measurements were taken for all students. Prevalence of metabolic syndrome was estimated based on the National Cholesterol Education Program's Adult Treatment Panel III guidelines. Multivariable analysis was used to assess the prevalence of metabolic risk components. To explore the association between metabolic risk factors and lifestyle behaviors, students filled out a validated online questionnaire related to their eating habits, physical activity, and sleep patterns. Metabolic syndrome was not prevalent in our sample. However, about one-third of the students had at least one metabolic abnormality, and 6.0% had two metabolic abnormalities. The most common metabolic abnormalities were low HDL-cholesterol levels (22.0%) and high waist circumference (12.6%), and elevated serum triglyceride (5.8%). Adjusting for other factors, excess adiposity and high visceral fat scores were associated with increased risk of metabolic risk factors, whereas healthy lifestyle practices such as daily breakfast consumption, eating three meals a day, being active, and not smoking were associated with lower risks for MetS. Given the adverse consequences of undiagnosed metabolic abnormalities, efforts to identify and manage MetS among asymptomatic college students, particularly women, is essential and warrants further research.

Nutrition Status of Primary School Students in Two Rural Regions of Guinea-Bissau.

BACKGROUND: The nutrition status of primary schoolchildren in Africa has received relatively little attention in comparison to that of younger children. We surveyed primary school students in Guinea-Bissau, a nation that is among the poorest in the world. OBJECTIVE: Anthropometry and prevalence of anemia and vitamin A deficiency were assessed in schoolchildren participating in International Partnership for Human Development's school feeding program in 2 regions of Guinea-Bissau. METHODS: A cross-sectional survey of 32 schools in the regions of Cacheu and Oio was conducted in November 2011. Variables included age, gender, weight, height, hemoglobin, and retinol-binding protein concentrations. Z scores for height for age (HAZ), body mass index for age (BAZ), and weight for age were calculated using World Health Organization reference data. RESULTS: Anthropometric assessment of 4784 students revealed stunting (HAZ < -2) in 15.5%, thinness (BAZ < -2) in 13.2%, and anemia in 42.0%. Stunting, thinness, and anemia were significantly more common in males, in students from Oio, and in older students. Vitamin A deficiency, detected in 21.5% of the population, was the only assessment that did not demonstrate significant differences between genders or regions. About 61.1% of all children had 1 or more indicators of undernutrition. CONCLUSION: There are substantial rates of stunting, thinness, underweight, anemia, and vitamin A deficiency in primary schoolchildren in Guinea-Bissau, even among those participating in a school lunch program and particularly among males and older students. The results suggest the need for evaluating feeding programs and other methods to improve nutrition status in primary school students, especially in older students.

Level of nutrition knowledge and its association with fat consumption among college students.

BACKGROUND: Intake of saturated fat, trans fat, and cholesterol has been associated with increased risk of coronary heart disease. The aim of this study was to explore whether increased nutrition knowledge is associated with a reduction in the consumption of unhealthy fats in a sample of university students. METHODS: A sample of 231 students, with a mean age of 20 years, was recruited from university campus during spring 2012. Students completed a validated questionnaire related to students' demographic, nutrition knowledge, and daily fat consumption. Weight, height, and waist circumference were measured. Data were analyzed using one-way ANOVA, chi-square, and student's t-test. RESULTS: Results indicate that female students have greater nutrition knowledge than male students (the mean nutrition score for women was 5 points higher than that of men (P = 0.01)). Nutrition knowledge was negatively correlated with fat and cholesterol intake. Students who consumed more than 35 % calories from fat or >300 mg of cholesterol daily had lower mean nutrition scores than those students with lower fat or cholesterol intake (8 points lower and 7.9 points lower, respectively). Using linear regression for nutrition scores on estimated saturated fat intake and cholesterol intake (controlling for gender, height, weight, age, and dieting), nutrition scores were negatively associated with saturated fat intake (-0.15, P <0.0001) and cholesterol intake (-1.38, P <0.0001). CONCLUSION: Students with greater nutritional knowledge consumed less unhealthy fats and cholesterol. This finding magnifies the role of nutrition education as a potential tool in health campaigns to promote healthy eating patterns among college students. Results of this pilot study can inform the design of future nutrition education intervention studies to assess the efficacy of nutrition knowledge on pattern of fat consumption among college students.

A Survey of Adverse Event Reporting Practices Among US Healthcare Professionals.

INTRODUCTION: The under-reporting of adverse drug events (ADEs) is an international health concern. A number of studies have assessed the root causes but, to our knowledge, little information exists relating under-reporting to practices and systems used for the recording and tracking of drug-related adverse event observations in ambulatory settings, institutional settings, and retail pharmacies. OBJECTIVES: Our objective was to explore the process for reporting ADEs in US hospitals, ambulatory settings, and retail pharmacies; to explore gaps and inconsistencies in the reporting process; and to identify the causes of under-reporting ADEs in these settings. METHODS: The Tufts Center for the Study of Drug Development (Tufts CSDD) interviewed 11 thought leaders and conducted a survey between May and August 2014 among US-based healthcare providers (HCPs) in diverse settings to assess their experiences with, and processes for, reporting ADEs. RESULTS: A total of 123 individuals completed the survey (42 % were pharmacists; 27 % were nurses; 15 % were physicians; and 16 % were classified as 'other'). HCPs indicated that the main reasons for under-reporting were difficulty in determining the cause of the ADE, given that most patients receive multiple therapies simultaneously (66 % of respondents); that HCPs lack sufficient time to report ADEs (63 % of respondents); poor integration of ADE-reporting systems (53 % of respondents); and uncertainty about reporting procedures (52 % of respondents). DISCUSSION: The results of this pilot study identify that key factors contributing to the under-reporting of ADEs relate to a lack of standardized process, a lack of training and education, and a lack of integrated health information technologies.

A Randomized Cross-over Air Filtration Intervention Trial for Reducing Cardiovascular Health Risks in Residents of Public Housing near a Highway.

Exposure to traffic-generated ultrafine particles (UFP; particles <100 nm) is likely a risk factor for cardiovascular disease. We conducted a trial of high-efficiency particulate arrestance (HEPA) filtration in public housing near a highway. Twenty residents in 19 apartments living <200 m from the highway participated in a randomized, double-blind crossover trial. A HEPA filter unit and a particle counter (measuring particle number concentration (PNC), a proxy for UFP) were installed in living rooms. Participants were exposed to filtered air for 21 days and unfiltered air for 21 days. Blood samples were collected and blood pressure measured at days 0, 21 and 42 after a 12-hour fasting period. Plasma was analyzed for high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor alpha-receptor II (TNF-RII) and fibrinogen. PNC reductions ranging from 21% to 68% were recorded in 15 of the apartments. We observed no significant differences in blood pressure or three of the four biomarkers (hsCRP, fibrinogen, and TNF-RII) measured in participants after 21-day exposure to HEPA-filtered air compared to measurements after 21-day exposure to sham-filtered air. In contrast, IL-6 concentrations were significantly higher following HEPA filtration (0.668 pg/mL; CI = 0.465-0.959) compared to sham filtration. Likewise, PNC adjusted for time activity were associated with increasing IL-6 in 14- and 21-day moving averages, and PNC was associated with decreasing blood pressure in Lags 0, 1 and 2, and in a 3-day moving average. These negative associations were unexpected and could be due to a combination of factors including exposure misclassification, unsuccessful randomization (i.e., IL-6 and use of anti-inflammatory medicines), or uncontrolled confounding. Studies with greater reduction in UFP levels and larger sample sizes are needed. There also needs to be more complete assessment of resident time activity and of outdoor vs. indoor source contributions to UFP exposure. HEPA filtration remains a promising, but not fully realized intervention.

Predictors of hypophosphatemia during refeeding of patients with severe anorexia nervosa.

OBJECTIVE: Hypophosphatemia of refeeding is one of the most dangerous complications seen during the treatment of patients with anorexia nervosa. Although easily detectable and treatable, hypophosphatemia is under-recognized as a complication of refeeding. Specific risk factors for the development of hypophosphatemia are likely to exist among patients with severe anorexia nervosa. The purpose of this study was to identify clinically useful markers that may predict the development of or protection from hypophosphatemia during refeeding. METHODS: We conducted a retrospective case-control study of 123 patients with severe anorexia nervosa admitted for medical stabilization at the ACUTE Center for Eating Disorders between October 1, 2008 and December 31, 2013. Risk factors for refeeding hypophosphatemia were determined by multivariate logistic regression from clinical parameters and laboratory values measured at the time of admission. RESULTS: The prevalence of hypophosphatemia was 33.3% (41 of 123 patients). Higher hemoglobin was the only risk factor associated with a higher odds of developing hypophosphatemia (adjusted odds ratio [aOR], 1.56 [95% confidence interval [CI], 1.12-2.18]). Statistically significant protective factors against the development of hypophosphatemia were observed with higher body mass index (aOR, 0.54 [95% CI, 0.39-0.75]), higher serum potassium (aOR, 0.29 [95% CI, 0.14-0.62]), and higher serum prealbumin (aOR, 0.91 [95% CI, 0.84-0.99]). DISCUSSION: Four independent factors associated with refeeding hypophosphatemia were identified. Identification of findings which correlate with hypophosphatemia, or the lack thereof, has the potential to facilitate appropriate triage of patients with anorexia nervosa for closer monitoring during refeeding.

Identifying and Quantifying the Accuracy of Product Name Attribution of US-Sourced Adverse Event Reports in MedWatch of Somatropins and Insulins.

BACKGROUND: As of 2014, the US FDA was considering policy options to promote accurate attribution of adverse events for biosimilars. In order to assess the identification and traceability of biologics from multiple sources, Tufts University's Center for the Study of Drug Development conducted a study reviewing the current FDA Adverse Event Reporting System (FAERS) for reports related to insulin and growth hormone products. METHODS: For this study, all primary suspect reports that were received by FAERS for human growth hormone (hGH) and human insulin between the fourth quarter of 2005 and the third quarter of 2013 were extracted and analyzed. RESULTS: The rates of "accurate" brand (ie, identifiable) drug names were generally high, with a higher incidence for hGH drugs than for insulin drugs (92% of hGH primary suspect reports vs 84% of insulin primary suspect reports). Lot number completion rates were generally low, with a higher incidence for insulin drugs than for hGH drugs (37% of insulin primary suspect reports vs 13% of hGH primary suspect reports). There were 13.5% of insulin reports that could not be linked to manufacturers, while 7.5% of hGH reports could not be linked to a manufacturer. CONCLUSIONS: The completion and accuracy rates of FAERS data on biologics observed in this study are consistent with those observed in earlier studies and suggest that traceability in adverse event reports can be improved through more consistent use of brand names or other product specific identifiers and through more frequent inclusion of lot numbers.

The value of a safety-net hospital case example: Denver Health.

Mergers in the health care are common. The safety nets are being left out, because the operating margins of these hospitals are too thin. The Accountable Care Act (ACA) may increase the financial challenges of safety nets. This is because uncompensated care disbursements such as funding of the disproportionate share hospitals are scheduled to phase down as ACA implementation proceeds. If the safety nets became financially unstable, this would destabilize the local hospital market. Denver Health has gained national recognition for its innovations and excellent quality of care. This article will promote an awareness that safety-net hospitals should be considered for collaborations.

Bacterial contamination of healthcare workers' uniforms: a randomized controlled trial of antimicrobial scrubs.

BACKGROUND: Healthcare workers' (HCWs) uniforms become contaminated with bacteria during normal use, and this may contribute to hospital-acquired infections. Antimicrobial uniforms are currently marketed as a means of reducing this contamination. OBJECTIVE: To compare the extent of bacterial contamination of uniforms and skin when HCWs wear 1 of 2 antimicrobial scrubs or standard scrubs. DESIGN: Prospective, randomized, controlled trial. SETTING: University-affiliated, public safety net hospital PARTICIPANTS: Hospitalist physicians, nurse practitioners, physician assistants, housestaff, and nurses (total N = 105) working on internal medicine units. INTERVENTION: Subjects were randomized to wear standard scrubs or 1 of 2 antimicrobial scrubs. MEASUREMENTS: Bacterial colony counts in cultures taken from the HCWs' scrubs and wrists after an 8-hour workday. RESULTS: The median (interquartile range) total colony counts was 99 (66-182) for standard scrubs, 137 (84-289) for antimicrobial scrub type A, and 138 (62-274) for antimicrobial scrub type B (P = 0.36). Colony counts from participants' wrists were 16 (5-40) when they wore standard scrubs and 23 (4-42) and 15 (6-54) when they wore antimicrobial scrubs A and B, respectively (P = 0.92). Resistant organisms were cultured from 3 HCWs (4.3%) randomized to antimicrobial scrubs and none randomized to standard scrubs (P = 0.55). Six participants (5.7%) reported side effects to wearing scrubs, all of whom wore antimicrobial scrubs (P = 0.18). CONCLUSIONS: We found no evidence that either antimicrobial scrub product decreased bacterial contamination of HCWs' uniforms or skin after an 8-hour workday.

Medical complications of self-induced vomiting.

Bulimia nervosa, often characterized by self-induced vomiting, is complicated by medical manifestations that affect nearly every organ system in the body. Effects range from superficial skin and dental findings to esophageal pathology, electrolyte abnormalities, cardiac arrhythmias, and in extreme cases, death. Ultimately, cessation of vomiting is necessary to cure most associated medical complications. Improper management of medical complications may lead to significant psychological distress to the patient. Fortunately, efficacious treatments do exist both to ease symptoms and ideally help the patient make a smooth transition to cessation of self-induced vomiting behavior.

The human ITPA polymorphic variant P32T is destabilized by the unpacking of the hydrophobic core.

Inosine triphosphate pyrophosphatase (ITPA), a key enzyme involved in maintaining the purity of cellular nucleoside triphosphate pools, specifically recognizes inosine triphosphate and xanthosine triphosphate (including the deoxyribose forms) and detoxifies them by catalyzing the hydrolysis of a phosphoanhydride bond, releasing pyrophosphate. This prevents their inappropriate use as substrates in enzymatic reactions utilizing (d)ATP or (d)GTP. A human genetic polymorphism leads to the substitution of Thr for Pro32 (P32T) and causes ITPA deficiency in erythrocytes, with heterozygotes having on average 22.5% residual activity, and homozygotes having undetectable activity. This polymorphism has been implicated in modulating patients' response to mercaptopurines and ribavirin. Human fibroblasts containing this variant have elevated genomic instability upon treatment with base analogs. We find that the wild-type and P32T forms are dimeric in solution and in the crystal structure. This abolishes the previous speculation that the P32T change disrupts dimerization as a mechanism of inactivation. The only difference in structure from the wild-type protein is that the area surrounding Thr32 is disrupted. Phe31 is flipped from the hydrophobic core out into the solvent, leaving a hole in the hydrophobic core of the protein which likely accounts for the reduced thermal stability of P32T ITPA and ultimately leads to its susceptibility to degradation in human cells. Circular dichroism and thermal denaturation studies confirm these structural results. We propose that the dimer of P32T variant subunit with wild-type subunit is degraded in cells similarly to the P32T homodimer explaining the level of loss of ITPA activity in heterozygotes.

Successful "detoxing" from commonly utilized modes of purging in bulimia nervosa.

Bulimia nervosa has many medical complications associated with the different modes of purging utilized by these patients. There also are inherent medical complications associated with chronic purging when these behaviors are abruptly discontinued. These complications experienced by a patient with bulimia nervosa when they decide to cease purging, can be a strong deterrent to successfully treating this disorder. Therefore it behooves care providers to become familiar with these complications in order to skillfully recommend strategies to help overcome the tendency to revert to purging behaviors.

Periadolescent rats (P41-50) exhibit increased susceptibility to D-methamphetamine-induced long-term spatial and sequential learning deficits compared to juvenile (P21-30 or P31-40) or adult rats (P51-60).

We have previously shown that P11-20 treatment with d-methamphetamine (MA) induces impaired spatial navigation in the Morris water maze (MWM), whereas P1-10 treatment does not. Little is known about the long-term behavioral consequences of MA during juvenile, adolescent, and early adult brain development. In dose-response experiments, we tested successive 10-day intervals of exposure to MA in rats (P21-30, P31-40, P41-50, and P51-60; four doses per day). MA dosing prior to P21 produces little or no toxicity; however, we observed an increased toxicity with advancing age. Across-age comparisons revealed no MWM acquisition or Cincinnati water maze (CWM) effects after MA treatment on P21-30 (2.5-10 mg/kg/dose), P31-40 (1.25-7.5 mg/kg/dose), or P51-60 (1.25-5.0 mg/kg/dose); however, significantly impaired MWM acquisition was observed after P41-50 MA treatment at the highest dose (6.25 mg/kg/dose). Learning in the CWM was also impaired in this group. No effects were seen at 1.25, 2.5, or 5 mg/kg/dose following P41-50 MA treatment. MWM reversal learning trials after P41-50 treatment showed a trend towards longer latency in all MA dose groups, but no effect on double-reversal trials. Reversal and double-reversal also showed no effects at the other exposure ages. No differences in straight channel swimming or cued learning in the MWM were seen after MA treatment at any exposure age. P41-50 is the periadolescent stage of brain development in rodents. The effects observed at this age may suggest a previously unrecognized period of susceptibility for MA-induced cognitive deficits.

Absorption and clearance of +/-3,4-methylenedioxymethamphetamine from the plasma of neonatal rats.

A limited number of studies exist describing the effects of +/-3,4-methylenedioxymethamphetamine (MDMA) during perinatal development, although the number of MDMA users has increased dramatically, and this increase is greatest in people of child-bearing age. Previous experimental studies show that exposure to MDMA during part of the third trimester-equivalent (postnatal days P1-20 in rats) cause two distinct types of learning and memory deficits (sequential and spatial) if exposed on P11-20, but not if exposure occurs on P1-10. In the present study, we examined differences in the ability of neonatal rats to eliminate MDMA. Rat offspring were given a single dose of 20 mg/kg MDMA on either P1 or 11, and plasma was collected at 1 of 10 time points during a 10-h period. MDMA concentrations were assessed by liquid chromatography/mass spectrometry (LC/MS). Indices of absorption did not differ as a function of exposure age. Exposure age differences in the clearance rate and half-life of MDMA were observed, such that the P1-treated animals had a significantly more rapid clearance and a shorter half-life than P11-treated animals did. These changes are in the same direction as the behavioral differences reported previously between P1-10 and P11-20 MDMA exposure groups. However, the pharmacokinetic differences were not commensurate with the behavioral changes in that the clearance differences at the two ages are quantitative whereas the behavioral differences were qualitative (no effects from P1-10 exposure and large effects from P11-20). Although the data do not suggest a mechanism for the learning deficits, they indicate that pharmacokinetic differences may contribute to the effects seen when exposure is begun on P11.