Risk of Adverse Birth Outcomes in Two Cohorts of Pregnant Women With HIV in Zambia.

BACKGROUND: A trial of progesterone to prevent preterm birth among HIV-infected Zambian women [Improving Pregnancy Outcomes with Progesterone (IPOP)] found no treatment effect, but the risk of the primary outcome was among the lowest ever documented in women with HIV. In this secondary analysis, we compare the risks of preterm birth (<37 weeks), stillbirth, and a composite primary outcome comprising the two in IPOP versus an observational pregnancy cohort [Zambian Preterm Birth Prevention Study (ZAPPS)] in Zambia, to evaluate reasons for the low risk in IPOP. METHODS: Both studies enrolled women before 24 gestational weeks, during August 2015-September 2017 (ZAPPS) and February 2018-January 2020 (IPOP). We used linear probability and log-binomial regression to estimate risk differences and risk ratios (RR), before and after restriction and standardization with inverse probability weights. RESULTS: The unadjusted risk of composite outcome was 18% in ZAPPS (N = 1450) and 9% in IPOP (N = 791) (RR = 2.0; 95% CI = 1.6, 2.6). After restricting and standardizing the ZAPPS cohort to the distribution of IPOP baseline characteristics, the risk remained higher in ZAPPS (RR = 1.6; 95% CI = 1.0, 2.4). The lower risk of preterm/stillbirth in IPOP was only partially explained by measured risk factors. CONCLUSIONS: Possible benefits in IPOP of additional monetary reimbursement, more frequent visits, and group-based care warrant further investigation.

AI Estimation of Gestational Age from Blind Ultrasound Sweeps in Low-Resource Settings.

BACKGROUND: Ultrasound is indispensable to gestational age estimation and thus to quality obstetrical care, yet high equipment cost and the need for trained sonographers limit its use in low-resource settings. METHODS: From September 2018 through June 2021, we recruited 4695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound sweeps (cineloop videos) of the gravid abdomen alongside standard fetal biometry. We trained a neural network to estimate gestational age from the sweeps and, in three test data sets, assessed the performance of the artificial intelligence (AI) model and biometry against previously established gestational age. RESULTS: In our main test set, the mean absolute error (MAE) (±SE) was 3.9±0.12 days for the model versus 4.7±0.15 days for biometry (difference, -0.8 days; 95% confidence interval [CI], -1.1 to -0.5; P<0.001). The results were similar in North Carolina (difference, -0.6 days; 95% CI, -0.9 to -0.2) and Zambia (-1.0 days; 95% CI, -1.5 to -0.5). Findings were supported in the test set of women who conceived by in vitro fertilization (MAE of 2.8±0.28 vs. 3.6±0.53 days for the model vs. biometry; difference, -0.8 days; 95% CI, -1.7 to 0.2) and in the set of women from whom sweeps were collected by untrained users with low-cost, battery-powered devices (MAE of 4.9±0.29 vs. 5.4±0.28 days for the model vs. biometry; difference, -0.6; 95% CI, -1.3 to 0.1). CONCLUSIONS: When provided blindly obtained ultrasound sweeps of the gravid abdomen, our AI model estimated gestational age with accuracy similar to that of trained sonographers conducting standard fetal biometry. Model performance appears to extend to blind sweeps collected by untrained providers in Zambia using low-cost devices. (Funded by the Bill and Melinda Gates Foundation.).

Limiting adverse birth outcomes in resource-limited settings (LABOR): protocol of a prospective intrapartum cohort study.

Background: Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention. Methods: The Limiting Adverse Birth Outcomes in Resource-Limited Settings (LABOR) Study is a multi-country, prospective, observational cohort designed to exhaustively document the course and outcomes of labor, delivery, and the immediate postpartum period in settings where adverse outcomes are frequent. The study is conducted at four hospitals across three countries in Ghana, India, and Zambia. We will enroll approximately 12,000 women at presentation to the hospital for delivery and follow them and their fetuses/newborns throughout their labor and delivery course, postpartum hospitalization, and up to 42 days thereafter. The co-primary outcomes are composites of maternal (death, hemorrhage, hypertensive disorders, infection) and fetal/neonatal adverse events (death, encephalopathy, sepsis) that may be attributed to the intrapartum period. The study collects extensive physiologic data through the use of physiologic sensors and employs medical scribes to document examination findings, diagnoses, medications, and other interventions in real time. Discussion: The goal of this research is to produce a large, sharable dataset that can be used to build statistical algorithms to prospectively stratify parturients according to their risk of adverse outcomes. We anticipate this research will inform the development of new tools to reduce peripartum morbidity and mortality in low-resource settings.

Weekly 17 alpha-hydroxyprogesterone caproate to prevent preterm birth among women living with HIV: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV. METHODS: We did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete. FINDINGS: Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI -3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported. INTERPRETATION: Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation. FUNDING: US National Institutes of Health and the Bill and Melinda Gates Foundation.

GIS-Based Home Neighborhood Food Outlet Counts, Street Connectivity, and Frequency of Use of Neighborhood Restaurants and Food Stores.

Researchers have linked neighborhood food availability to the overall frequency of using food outlets without noting if those outlets were within or outside of participants' neighborhoods. We aimed to examine the association of neighborhood restaurant and food store availability with frequency of use of neighborhood food outlets, and whether such an association was modified by neighborhood street connectivity using a large and diverse population-based cohort of middle-aged U.S. adults. We used self-reported frequency of use of fast food restaurants, sit-down restaurants, and grocery stores in respondents' home neighborhoods using data from the Coronary Artery Risk Development in Young Adults study Year 20 exam in 2005-2006 (n = 2860; Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA) and geographically matched GIS-measured neighborhood-level food resource, street, and U.S. Census data. We used mixed-effects logistic regression to examine the associations of the GIS-measured count of neighborhood fast food restaurants, sit-down restaurants, and grocery stores with self-reported frequency of using neighborhood restaurants and food stores and whether such associations differed by GIS-measured neighborhood street connectivity among those who perceived at least one such food outlet. In multivariate analyses, we observed a positive association between the GIS-measured count of neighborhood sit-down restaurants (OR = 1.02, 95% CI 1.00-1.04) and the self-reported frequency of using neighborhood sit-down restaurants. We observed no statistically significant association between GIS-measured count of neighborhood fast food restaurants and self-reported frequency of using neighborhood fast food restaurants, nor did we observe a statistically significant association between GIS-measured count of neighborhood grocery stores and self-reported frequency of using neighborhood grocery stores. We observed inverse associations between GIS-measured neighborhood street connectivity and the self-reported frequencies of using neighborhood fast food restaurants (OR = 0.42, 95% CI 0.26-0.68) and grocery stores (OR = - 2.26, 95% CI - 4.52 to - 0.01). Neighborhood street connectivity did not modify the association between GIS-measured neighborhood restaurant and food store count and the self-reported frequency of using neighborhood restaurants and food stores. Our findings suggest that, for those who perceived at least one sit-down restaurant in their neighborhood, individuals who have more GIS-measured sit-down restaurants in their neighborhoods reported more frequent use of sit-down restaurants than those whose neighborhoods contain fewer such restaurants. Our results also suggest that, for those who perceived at least one fast food restaurant in their neighborhood, individuals who live in neighborhoods with greater GIS-measured street connectivity reported less use of neighborhood fast food restaurants than those who live in neighborhoods with less street connectivity. The count of neighborhood sit-down restaurants and the connectivity of neighborhood street networks appear important in understanding the use of neighborhood food resources.

The links between agriculture, Anopheles mosquitoes, and malaria risk in children younger than 5 years in the Democratic Republic of the Congo: a population-based, cross-sectional, spatial study.

BACKGROUND: The relationship between agriculture, Anopheles mosquitoes, and malaria in Africa is not fully understood, but it is important for malaria control as countries consider expanding agricultural projects to address population growth and food demand. Therefore, we aimed to assess the effect of agriculture on Anopheles biting behaviour and malaria risk in children in rural areas of the Democratic Republic of the Congo (DR Congo). METHODS: We did a population-based, cross-sectional, spatial study of rural children (<5 years) in the DR Congo. We used information about the presence of malaria parasites in each child, as determined by PCR analysis of dried-blood spots from the 2013-14 DR Congo Demographic and Health Survey (DHS). We also used data from the DHS, a longitudinal entomological study, and available land cover and climate data to evaluate the relationships between agriculture, Anopheles biting behaviour, and malaria prevalence. Satellite imagery was used to measure the percentage of agricultural land cover around DHS villages and Anopheles sites. Anopheles biting behaviour was assessed by Human Landing Catch. We used probit regression to assess the relationship between agriculture and the probability of malaria infection, as well as the relationship between agriculture and the probability that a mosquito was caught biting indoors. FINDINGS: Between Aug 13, 2013, and Feb 13, 2014, a total of 9790 dried-blood spots were obtained from the DHS, of which 4612 participants were included in this study. Falciparum malaria infection prevalence in rural children was 38·7% (95% uncertainty interval [UI] 37·3-40·0). Increasing exposure to agriculture was associated with increasing malaria risk with a high posterior probability (estimate 0·07, 95% UI -0·04 to 0·17; posterior probability [estimate >0]=0·89), with the probability of malaria infection increased between 0·2% (95% UI -0·1 to 3·4) and 2·6% (-1·5 to 6·6) given a 15% increase in agricultural cover, depending on other risk factors. The models predicted that large increases in agricultural cover (from 0% to 75%) increase the probability of infection by as much as 13·1% (95% UI -7·3 to 28·9). Increased risk might be due to Anopheles gambiae sensu lato, whose probability of biting indoors increased between 11·3% (95% UI -15·3 to 25·6) and 19·7% (-12·1 to 35·9) with a 15% increase in agriculture. INTERPRETATION: Malaria control programmes must consider the possibility of increased risk due to expanding agriculture. Governments considering initiating large-scale agricultural projects should therefore also consider accompanying additional malaria control measures. FUNDING: National Institutes of Health, National Science Foundation, Bill & Melinda Gates Foundation, President's Malaria Initiative, and Royster Society of Fellows at the University of North Carolina at Chapel Hill.

Neighborhood Sociodemographics and Change in Built Infrastructure.

While increasing evidence suggests an association between physical infrastructure in neighbourhoods and health outcomes, relatively little research examines how neighbourhoods change physically over time and how these physical improvements are spatially distributed across populations. This paper describes the change over 25 years (1985-2010) in bicycle lanes, off-road trails, bus transit service, and parks, and spatial clusters of changes in these domains relative to neighbourhood sociodemographics in four U.S. cities that are diverse in terms of geography, size and population. Across all four cities, we identified increases in bicycle lanes, off-road trails, and bus transit service, with spatial clustering in these changes that related to neighbourhood sociodemographics. Overall, we found evidence of positive changes in physical infrastructure commonly identified as supportive of physical activity. However, the patterning of infrastructure change by sociodemographic change encourages attention to the equity in infrastructure improvements across neighbourhoods.

Municipal investment in off-road trails and changes in bicycle commuting in Minneapolis, Minnesota over 10 years: a longitudinal repeated cross-sectional study.

BACKGROUND: We studied the effect of key development and expansion of an off-road multipurpose trail system in Minneapolis, Minnesota between 2000 and 2007 to understand whether infrastructure investments are associated with increases in commuting by bicycle. METHODS: We used repeated measures regression on tract-level (N = 116 tracts) data to examine changes in bicycle commuting between 2000 and 2008-2012. We investigated: 1) trail proximity measured as distance from the trail system and 2) trail potential use measured as the proportion of commuting trips to destinations that might traverse the trail system. All analyses (performed 2015-2016) adjusted for tract-level sociodemographic covariates and contemporaneous cycling infrastructure changes (e.g., bicycle lanes). RESULTS: Tracts that were both closer to the new trail system and had a higher proportion of trips to destinations across the trail system experienced greater 10-year increases in commuting by bicycle. CONCLUSIONS: Proximity to off-road infrastructure and travel patterns are relevant to increased bicycle commuting, an important contributor to overall physical activity. Municipal investment in bicycle facilities, especially off-road trails that connect a city's population and its employment centers, is likely to lead to increases in commuting by bicycle.

Obtaining Longitudinal Built Environment Data Retrospectively across 25 years in Four US Cities.

BACKGROUND: Neighborhood transportation infrastructure and public recreational facilities are theorized to improve the activity, weight, and cardiometabolic profiles of individuals living in close proximity to these resources. However, owing to data limitations, there has not been adequate study of the influence of timing and placement of new infrastructure on health over time. METHODS: This protocol details methods of the four cities study to perform retrospective field audits in order to capitalize on existing longitudinal health data from the coronary artery risk development in young adults (CARDIA) study. We developed and verified measures of recreation facilities (trails, parks) and transportation infrastructure (bus, light rail, bicycle parking, bicycle paths) in Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA (USA). We identify introductions, renovations, and closures between 1985 and 2010 to develop measures of facility and infrastructure change. Ultimately, these data were linked to CARDIA sites' respondents' geographic locations over the 25-year study period to examine associations with health behaviors and outcomes. RESULTS: Data available for retrospective audits was inconsistent by city, primarily due to record-keeping differences. We found large increases in bicycle infrastructure, with the exception of Birmingham, AL, USA. Excluding the addition of a new rail line in Minneapolis, MN, USA, few changes occurred in bus service, rail, and parks. CONCLUSION: Our method represents innovation toward the collection of retrospective neighborhood data for use in longitudinal analyses. The data produced give insight into the way neighborhood infrastructure has changed over time and the potential relationship between these changes and health behaviors.

Promoting the Congregate Meal Program to the Next Generation of Rural-Residing Older Adults.

Despite a growing older adult population, Iowa Congregate Meal Program (CMP) participation has declined. Motivators and barriers to congregate mealsite participation and wellness programming preferences of baby boomers and older adults were examined to provide insight to how to revise and better promote the CMP for the next generation of older adults. Four focus group sessions were conducted with 27 primarily White, rural-residing adults, ages 48-88 years. Participation motivators included educational programs, food, and socialization while barriers included negative perceptions and stereotypes associated with congregate mealsites. Desired wellness programs were viewed as interactive and relevant. Healthcare was the leading wellness need with financial management and physical activity cited as the most-wanted topics of wellness programs. These results provide insight on factors, aside from funding, that may be adversely impacting CMP participation and identifies areas for further investigation.

Spatial-temporal modeling of neighborhood sociodemographic characteristics and food stores.

The literature on food stores, neighborhood poverty, and race/ethnicity is mixed and lacks methods of accounting for complex spatial and temporal clustering of food resources. We used quarterly data on supermarket and convenience store locations from Nielsen TDLinx (Nielsen Holdings N.V., New York, New York) spanning 7 years (2006-2012) and census tract-based neighborhood sociodemographic data from the American Community Survey (2006-2010) to assess associations between neighborhood sociodemographic characteristics and food store distributions in the Metropolitan Statistical Areas (MSAs) of 4 US cities (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and San Francisco, California). We fitted a space-time Poisson regression model that accounted for the complex spatial-temporal correlation structure of store locations by introducing space-time random effects in an intrinsic conditionally autoregressive model within a Bayesian framework. After accounting for census tract-level area, population, their interaction, and spatial and temporal variability, census tract poverty was significantly and positively associated with increasing expected numbers of supermarkets among tracts in all 4 MSAs. A similar positive association was observed for convenience stores in Birmingham, Minneapolis, and San Francisco; in Chicago, a positive association was observed only for predominantly white and predominantly black tracts. Our findings suggest a positive association between greater numbers of food stores and higher neighborhood poverty, with implications for policy approaches related to food store access by neighborhood poverty.

Synthesis and characterization of a new binucleating tetraphosphine ligand based on 1,2-phenylene chelates and the structures of dinickel tetrachloride complexes of the ligand.

A new binucleating tetraphosphine ligand, rac- and meso-(Et2P-1,2-C6H4)P(Ph)CH2(Ph)P(1,2-C6H4PEt2) (et,ph-P4-Ph), has been synthesized. Separation and purification of the ligand diastereomers have been accomplished via column chromatography. Ni2Cl4(et,ph-P4-Ph) complexes of both diastereomers have been prepared in high yield and crystallographically characterized.

Impact of new-onset persistent left bundle branch block on late clinical outcomes in patients undergoing transcatheter aortic valve implantation with a balloon-expandable valve.

OBJECTIVES: The aim of this study was to determine the impact of new-onset persistent left bundle branch block (NOP-LBBB) on late outcomes after transcatheter aortic valve implantation (TAVI). BACKGROUND: The impact of NOP-LBBB after TAVI remains controversial. METHODS: A total of 668 consecutive patients who underwent TAVI with a balloon-expandable valve without pre-existing LBBB or permanent pacemaker implantation (PPI) were included. Electrocardiograms were obtained at baseline, immediately after the procedure, and daily until hospital discharge. Patients were followed at 1, 6, and 12 months and yearly thereafter. RESULTS: New-onset LBBB occurred in 128 patients (19.2%) immediately after TAVI and persisted at hospital discharge in 79 patients (11.8%). At a median follow-up of 13 months (range 3 to 27 months), there were no differences in mortality rate between the NOP-LBBB and no NOP-LBBB groups (27.8% vs. 28.4%; adjusted-hazard ratio: 0.87 [95% confidence interval (CI): 0.55 to 1.37]; p = 0.54). There were no differences between groups regarding cardiovascular mortality (p = 0.82), sudden death (p = 0.87), rehospitalizations for all causes (p = 0.11), or heart failure (p = 0.55). NOP-LBBB was the only factor associated with an increased rate of PPI during the follow-up period (13.9% vs. 3.0%; hazard ratio: 4.29 [95% CI: 2.03 to 9.07], p < 0.001. NOP-LBBB was also associated with a lack of left ventricular ejection fraction improvement and poorer New York Heart Association functional class at follow-up (p < 0.02 for both). CONCLUSIONS: NOP-LBBB occurred in ∼1 of 10 patients who had undergone TAVI with a balloon-expandable valve. NOP-LBBB was associated with a higher rate of PPI, a lack of improvement in left ventricular ejection fraction, and a poorer functional status, but did not increase the risk of global or cardiovascular mortality or rehospitalizations at 1-year follow-up.

Community-based exergaming program increases physical activity and perceived wellness in older adults.

Exergaming may be an effective strategy to increase physical activity participation among rural older adults. This pilot project examined the effects of a 24-wk exergaming and wellness program (8 wk onsite exergaming, 16-wk wellness newsletter intervention) on physical activity participation and subjective health in 46 rural older adults. Sociodemographic data and self-reported physical activity were analyzed using descriptive statistics and Cochran's Q, respectively. Qualitative data were reviewed, categorized on the basis of theme, and tabulated for frequency. Increased physical activity and perceived health were the most reported perceived positive changes. Significant increases in physical activity participation were maintained among participants who were physically inactive at baseline. Best-liked features were physical activity and socialization. Findings suggest that this pilot exergaming and wellness program is effective in increasing physical activity in sedentary rural older adults, increasing socialization, and increasing subjective physical health among rural older adults.

The effect of pentoxifylline and its metabolite-1 on inflammation and fibrosis in the TNBS model of colitis.

TNBS-induced colitis has characteristics resembling human Crohn's disease including transmural inflammation, ulceration, and fibrosis. Current treatments target acute symptoms but do not necessarily prevent fibrotic complications of the disease. The aim of this study was to determine the effect of pentoxifylline and its primary metabolite (M-1) on fibrosis in the TNBS-induced colitis model. Myeloperoxidase activity and interleukin-18 are indicators of inflammation and were elevated in the TNBS model. The morphology damage score assesses colon damage and was also elevated in the TNBS model. Collagen as the indicator of fibrosis was quantified and visualized by the Sirius Red/Fast Green staining technique and collagen type I was assessed by Western analysis. Collagen was elevated in the TNBS-induced model. Pentoxifylline and M-1 treatment significantly attenuated colon damage and inflammation in TNBS-colitis (P<0.05). M-1 treatment significantly reduced the TNBS-induced increase in colon weight, colon thickness and total collagen content (P<0.05). Results suggest that pentoxifylline and M-1 inhibit intestinal fibrosis in this experimental model and may prove beneficial in the treatment of intestinal fibrosis associated with human Crohn's disease with the added benefit of inhibiting inflammation and ulceration. This is the first study to examine the effects of racemic M-1 in vivo and one of the few studies to examine the effect of drugs on both inflammation and fibrosis in an experimental model of colitis.

Effect of fetuin, a TGFbeta antagonist and pentoxifylline, a cytokine antagonist on hepatic stellate cell function and fibrotic parameters in fibrosis.

We have previously shown that monocyte conditioned medium (MCM) from patients with liver fibrosis stimulated proliferation of hepatic stellate cells (HSCs), the major cell involved in hepatic fibrosis. To investigate the potential role of fetuin and pentoxifylline in fibrosis we used MCM samples obtained from patients with biopsy proven hepatic fibrosis related to Hepatitis C (HCV). Our results indicate that the MCM obtained from patients with HCV-related liver fibrosis significantly stimulated collagen synthesis in HSCs as assessed by tritiated proline incorporation into a collagenase sensitive trichloroacetic acid (TCA) precipitate. Collagen synthesis was also stimulated in HSCs using transforming growth factor beta (TGFbeta) and this effect was neutralized using TGFbeta antibody. Incubation of HSCs with fetuin (but not TGFbeta antibody) significantly inhibited collagen synthesis in HSCs that were stimulated by HCV MCM samples. Patient MCM samples would also stimulate proliferation of HSCs as assessed by tritiated thymidine uptake but this effect was not attenuated by fetuin. Likewise the significant stimulatory effect of platelet derived growth factor (PDGF) on HSC proliferation and collagen synthesis was not inhibited by fetuin but could be significantly reduced by 70% and 40% respectively, when treated with pentoxifylline. We also investigated the ability of samples obtained from patients with hepatic fibrosis to inhibit HSC apoptosis, as determined by okadaic acid-induced 4-hydroxynonenal immunocytochemistry in HSCs. We have previously reported that okadaic acid induces apoptosis in HSCs as assessed by Hoescht and TUNEL. Okadaic acid treatment produced a positive 4-hydroxynonenal (4-HNE) immunoreactivity in HSCs and treatment with HCV patient MCM or TGFbeta decreased the 4-HNE positive immunoreactivity in HSCs treated with okadaic acid. Our results suggest that fetuin may be beneficial in hepatic fibrosis and suggest that combination of fetuin and pentoxifylline may target the two key events in hepatic fibrosis by modifying the effects of TGFbeta and PDGF, the two major growth factors in fibrosis.

A novel drug interaction between the quinolone antibiotic ciprofloxacin and a chiral metabolite of pentoxifylline.

Pentoxifylline (PTX), a methylxanthine derivative, is metabolized to seven compounds in vivo, with metabolites 1 and 5 possessing biologic activity. Metabolite-1 is a chiral molecule and its S-enantiomer is selectively formed during PTX metabolism in vivo. We have developed a reproducible method of synthesizing a racemic mixture of the chiral metabolite-1 (M-1) of PTX. In this study, we examined the kinetics of racemic M-1 in mice compared to PTX. An interaction between PTX and the quinolone antibiotic ciprofloxacin has been demonstrated. A goal of this study was to determine if a similar interaction occurs between ciprofloxacin and M-1 in vivo. M-1 and PTX had similar absorption and elimination rates. M-1 was rapidly converted to PTX, while very little PTX was converted to M-1 in vivo. The peak concentration of biologically active drug (PTX+M-1) was 36% higher when M-1 was administered compared to PTX. Combination of ciprofloxacin and PTX significantly increased serum concentrations of both PTX and M-1 (2-fold) compared to controls. The combination of M-1 and ciprofloxacin significantly increased serum concentration of M-1 (3-fold) and PTX (2-fold). The ciprofloxacin/M-1 combination produced a significantly higher sera concentration of bioactive drug compared to all other groups suggesting that this combination may enhance the anti-fibrogenic effect.

Reliability and validity of questions on the youth media campaign longitudinal survey.

PURPOSE: The study evaluated the reliability and validity of the physical activity questions in the Youth Media Campaign Longitudinal Survey (YMCLS), a nationally representative survey of 9- to 13-yr-old youth. METHODS: The participants were 192 youth aged 9-13 yr (93 males and 99 females) in grades 4-8 from eight schools in a large, ethnically diverse school district. Participants completed two YMCLS phone interviews, which were administered 1 wk apart by trained interviewers. Reliability was examined by comparing data from two administrations of the survey. Validity was examined by comparing YMCLS measures from the second administration with temporally matched measures from an accelerometer and a detailed activity log. RESULTS: Reliability coefficients were high for estimates of organized activity (intraclass correlation coefficient (ICC)=0.78) and moderate for estimates of free-time activity (ICC=0.60) and total weekly activity (ICC=0.60). Estimates of total weekly activity sessions were significantly correlated with the accelerometer (r=0.24) and the activity log (r=0.46). Estimates of activity time and activity sessions on the previous day were also significantly correlated with the accelerometer (r=0.53 and 0.37, respectively) and the activity log (r=0.37 and 0.47, respectively). Correlations between the YMCLS and the activity log were higher for organized activity (r=0.72) than for free-time activity (r=0.46). Reliability and validity coefficients were similar for boys and girls, but older youth (11-13 yr) had higher coefficients than younger students (9-10 yr). CONCLUSION: The YMCLS has acceptable reliability and validity for estimating habitual physical activity in youth aged 9-13 yr.

Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction.

In this study the drug interaction between ciprofloxacin (CIPRO) and pentoxifylline (PTX) was investigated and the role of CYP1A2 in the drug interaction was determined with the aid of a selective CYP1A2 inhibitor, furafylline (FURA), and the Cyp1A2 knockout mouse. Serum concentrations of PTX (83.4+/-1 micromol/l) and metabolite-1 (M-1) (13.7+/-2.8 micromol/l) following a single injection of PTX (100 mg/kg i.p.) were significantly higher (P<0.05) in mice treated with CIPRO (25 mg/kg i.p. 9 days) compared to serum concentrations of PTX (46.3+/-0.5 micromol/l) and M-1 (6.4+/-1.1 micromol/l) in mice administered saline. Murine hepatic microsomes were incubated with PTX alone or the combination of PTX and CIPRO. The metabolism of PTX in the murine hepatic microsomes containing both CIPRO and PTX was significantly decreased compared to microsomes incubated with PTX alone, suggesting that CIPRO may inhibit the metabolism of PTX. To further clarify the role of CYP1A2 in the metabolism of PTX in mice, the effect of a selective CYP1A2 mechanism based inhibitor, FURA, on the metabolism of PTX was investigated and our results indicate that FURA inhibited metabolism of PTX. We then investigated PTX elimination in the Cyp1A2 knockout mouse. Blood levels of PTX were assessed at 2 and 20 min following a single injection of PTX (32 mg/kg i.v). Serum concentration of PTX was determined in Cyp1A2 knockout mice compared to Cyp1A2 wild type control mice. The serum concentration of PTX in Cyp1A2 wild type mice (n=9) was 22.2+/-3.2 micromol/l at 20 min following injection of PTX. The serum concentration of PTX in Cyp1A2 knockout mice (n=11) was significantly elevated at 20 min following injection of PTX compared to Cyp1A2 wild type mice. These results clearly indicate that inhibition of CYP1A2 catalytic activity that occurs in the Cyp1A2 knockout mice is sufficient to alter metabolism of PTX and result in markedly elevated levels in serum of Cyp1A2 knockout mice. The results of Western analysis in murine microsomes suggest that CYP1A2 protein levels were not altered by CIPRO indicating that CIPRO did not downregulate Cyp1A2. The results of Western analysis also indicated that CIPRO treatment increased CYP2E1 in mouse microsomes and the implications of these will be discussed.

Selective down-regulation of c-jun gene expression by pentoxifylline and c-jun antisense interrupts platelet-derived growth factor signaling: pentoxifylline inhibits phosphorylation of c-Jun on serine 73.

Platelet-derived growth factor (PDGF) signals through several pathways, including mitogen-activated protein (MAP) kinase, Jun kinase, and C kinase, and stimulates proliferation of fibroblasts. Pentoxifylline inhibits PDGF-driven proliferation of fibroblasts. We have reported that pentoxifylline did not inhibit binding of PDGF to its specific cell-surface receptors or PDGF receptor phosphorylation. In this study, we investigated the effect of PDGF on the expression of c-fos and c-jun, because c-fos and c-jun form activator protein-1 complexes that stimulate genes involved in proliferation. We determined whether pentoxifylline would alter the expression of c-fos and c-jun. Our results indicate that PDGF induced the expression of both c-fos and c-jun. Pentoxifylline effectively reduced c-jun gene expression, which had been up-regulated by PDGF, but did not alter c-fos gene expression. The lack of effect on c-fos supports other studies from this laboratory, which indicate that pentoxifylline did not inhibit PDGF activation of MAP kinase. Treatment of fibroblasts with a phosphothioate c-jun antisense oligodeoxynucleotide reduced the levels of c-Jun protein and blocked PDGF-stimulated proliferation, suggesting a critical role for c-jun in PDGF-mediated proliferation. Combination of pentoxifylline and c-jun antisense suggested that they were likely inhibiting PDGF-stimulated proliferation at a single site in the PDGF signaling pathway. These results suggest that pentoxifylline inhibits PDGF-stimulated proliferation by selectively decreasing c-jun expression. To further define the mechanism of action of pentoxifylline, we assessed the effect of pentoxifylline on c-Jun and phosphorylated c-Jun immunoreactivity in cells treated with PDGF and cells that were transfected with wild-type c-jun plasmid using immunocytochemistry and Western blot analyses, and our results indicate that pentoxifylline inhibited phosphorylation of c-Jun on serine 73.