Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration.

Loss of significant intestinal length from congenital anomaly or disease may lead to short bowel syndrome (SBS); intestinal failure may be partially offset by a gain in epithelial surface area, termed adaptation. Current in vivo models of SBS are costly and technically challenging. Operative times and survival rates have slowed extension to transgenic models. We created a new reproducible in vivo model of SBS in zebrafish, a tractable vertebrate model, to facilitate investigation of the mechanisms of intestinal adaptation. Proximal intestinal diversion at segment 1 (S1, equivalent to jejunum) was performed in adult male zebrafish. SBS fish emptied distal intestinal contents via stoma as in the human disease. After 2 wk, S1 was dilated compared with controls and villus ridges had increased complexity, contributing to greater villus epithelial perimeter. The number of intervillus pockets, the intestinal stem cell zone of the zebrafish increased and contained a higher number of bromodeoxyuridine (BrdU)-labeled cells after 2 wk of SBS. Egf receptor and a subset of its ligands, also drivers of adaptation, were upregulated in SBS fish. Igf has been reported as a driver of intestinal adaptation in other animal models, and SBS fish exposed to a pharmacological inhibitor of the Igf receptor failed to demonstrate signs of intestinal adaptation, such as increased inner epithelial perimeter and BrdU incorporation. We describe a technically feasible model of human SBS in the zebrafish, a faster and less expensive tool to investigate intestinal stem cell plasticity as well as the mechanisms that drive intestinal adaptation.

Applications of PET imaging with the proliferation marker [18F]-FLT.

[18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease.

Cost-effectiveness of harm reduction in preventing hepatitis C among injection drug users.

OBJECTIVES: Hepatitis C (HCV) has emerged as a major epidemic among injection drug users (IDUs), with observed prevalence exceeding 70% in many American and European cities. This article explores the potential of syringe exchange programs (SEPs) to reduce HCV incidence and prevalence. DESIGN: A random-mixing epidemiological model is used to examine the potential impact of harm reduction interventions. METHODS: Steady-state analysis is used to scrutinize the impact of SEP on HCV incidence and prevalence and to examine the accuracy of short-term incidence analysis in predicting long-run program effects. RESULTS: SEP is predicted to have little impact on HCV incidence and prevalence within realistic populations of IDUs. CONCLUSIONS: Short-term incidence analysis substantially overstates SEP effectiveness and cost-effectiveness in preventing HCV. More comprehensive harm reduction models, coupled with referral of active IDUs to treatment, must complement syringe exchange to successfully contain highly infectious blood-borne diseases.

Syringe source, use, and discard among injection-drug users in New Haven, Connecticut.

We examined syringe source, use, and discard practices of injection-drug users (IDUs) in New Haven, Connecticut, a city with both a legal syringe-exchange program (SEP) and non-prescription availability of syringes through pharmacies. The population demographics, syringe use, and discard practices of IDUs who obtained syringes from various sources were compared using structured interview data. Of the 373 IDUs recruited, 268 (72 percent) resided in the city of New Haven. Among the New Haven IDUs, 111 (41 percent) reported pharmacies, 36 (13 percent) reported the New Haven SEP, 90 (34 percent) reported both, and 27 (10 percent) reported neither as their usual source of syringes in the past six months. No significant differences (p value < 0.05) were observed among New Haven IDUs who relied on pharmacies versus the SEP. However, IDUs who relied on the SEP were significantly less likely to report they threw away used syringes, compared with pharmacy users. Both the pharmacies and the New Haven SEP are important sources of sterile syringes for IDUs in New Haven. The lower frequency of syringe discard by IDUs who obtained their syringes primarily through the SEP indicates another public health benefit of programs such as these.

Sudden infant death syndrome, maternal smoking during pregnancy, and the cost-effectiveness of smoking cessation intervention.

OBJECTIVES: This study analyzed the relationship between prenatal maternal smoking and sudden infant death syndrome (SIDS) and examined the cost-effectiveness of smoking cessation interventions. METHODS: All recorded US singleton SIDS deaths from the 1995 birth cohort with birthweight exceeding 500 g were investigated. Infants with available maternal smoking data were matched with controls who survived to 1 year. Conditional logistic regression was used to estimate SIDS risks and accompanying cost-effectiveness. RESULTS: A total of 23.6% of singleton SIDS deaths appear to be attributable to prenatal maternal smoking. Typical cessation services available to all pregnant smokers could avert 108 SIDS deaths annually, at an estimated cost of $210,500 per life saved. CONCLUSIONS: Typical prenatal smoking cessation programs are highly cost-effective but have limited impact on the population incidence of SIDS.

Ignoring 'downstream infection' in the evaluation of harm reduction interventions for injection drug users.

Harm reduction interventions to reduce blood-borne disease incidence among injection drug users (IDUs). A common strategy to estimate the long-term impact of such interventions is to examine short-term incidence changes within a specific group of individuals exposed to the intervention. Such evaluations may overstate or understate long-term program effectiveness, depending upon the relationship between short-term and long-term incidence and prevalence. This short paper uses steady-state comparisons and a standard random-mixing model to scrutinize this evaluation approach. It shows that evaluations based upon short-term incidence changes can be significantly biased. The size and direction of the resulting bias depends upon a simple rule. For modest interventions, such analyses yield over-optimistic estimates of program effectiveness when steady-state disease prevalence exceeds 50% absent intervention. When steady-state prevalence is below 50%, such analyses display the opposite bias.

A competing risk model of sudden infant death syndrome incidence in two US birth cohorts.

OBJECTIVES: To compare changing incidence and changing risk factors associated with sudden infant death syndrome (SIDS) in the 1989 and 1996 US birth cohorts. STUDY DESIGN: All available singleton births over 500 g from the 1989 linked birth-infant death file and the 1996 and 1997 Perinatal Mortality files were examined. A log-logistic survival model was used to explicitly account for declining competing risks among low birth weight infants. RESULTS: Controlling for maternal prenatal smoking and other confounders, SIDS incidence declined by >33% between the 2 survey years (adjusted odds ratio = 0.628 with 95% CI [0.598, 0.660]). Self-reported declines in maternal prenatal smoking were also associated with significant declines in SIDS incidence. African American infants and infants born weighing <1000 g experienced increased relative risk compared with non-Hispanic white infants born weighing >2500 g. Hispanic/Latino infants had significantly lower SIDS risk than non-Hispanic white infants in both years. Accounting for declining competing risks and other factors, relative SIDS risks among infants born between 500 and 1000 g increased over the study period. CONCLUSIONS: SIDS incidence sharply declined between 1989 and 1996. High incidence of SIDS in African Americans and increased relative SIDS risk for infants born weighing <1000 g require increased attention from clinicians and public health policy makers.

Epidemic increase in childhood overweight, 1986-1998.

CONTEXT: Overweight is the most common health problem facing US children. Data for adults suggest that overweight prevalence has increased by more than 50% in the last 10 years. Data for children also suggest that the prevalence of overweight continues to increase rapidly. OBJECTIVE: To investigate recent changes in the prevalence of overweight within a nationally representative sample of children. DESIGN, SETTING, AND PARTICIPANTS: The National Longitudinal Survey of Youth, a prospective cohort study conducted from 1986 to 1998 among 8270 children aged 4 to 12 years (24 174 growth points were analyzed). MAIN OUTCOME MEASURES: Prevalence of overweight children, defined as body mass index (BMI) greater than the 95th percentile for age and sex, and prevalence of overweight and at-risk children, defined as BMI greater than the 85th percentile for age and sex. The roles of race/ethnicity, sex, income, and region of residence were also examined. RESULTS: Between 1986 and 1998, overweight increased significantly and steadily among African American (P<.001), Hispanic (P<.001), and white (P =.03) children. By 1998, overweight prevalence increased to 21.5% among African Americans, 21.8% among Hispanics, and 12.3% among non-Hispanic whites. In addition, overweight children were heavier in 1998 compared with 1986 (P<.001). After adjusting for confounding variables, overweight increased fastest among minorities and southerners, creating large demographic differences in the prevalence of childhood overweight by 1998. The number of children with BMI greater than the 85th percentile increased significantly from 1986 to 1998 among African American and Hispanic children (P<.001 for both) and nonsignificantly among white children (P =.77). CONCLUSIONS: Childhood overweight continues to increase rapidly in the United States, particularly among African Americans and Hispanics. Culturally competent treatment strategies as well as other policy interventions are required to increase physical activity and encourage healthy eating patterns among children.

Investing in youth tobacco control: a review of smoking prevention and control strategies.

OBJECTIVE: To provide a comprehensive review of interventions and policies aimed at reducing youth cigarette smoking in the United States, including strategies that have undergone evaluation and emerging innovations that have not yet been assessed for efficacy. DATA SOURCES: Medline literature searches, books, reports, electronic list servers, and interviews with tobacco control advocates. DATA SYNTHESIS: Interventions and policy approaches that have been assessed or evaluated were categorised using a typology with seven categories (school based, community interventions, mass media/public education, advertising restrictions, youth access restrictions, tobacco excise taxes, and direct restrictions on smoking). Novel and largely untested interventions were described using nine categories. CONCLUSIONS: Youth smoking prevention and control efforts have had mixed results. However, this review suggests a number of prevention strategies that are promising, especially if conducted in a coordinated way to take advantage of potential synergies across interventions. Several types of strategies warrant additional attention and evaluation, including aggressive media campaigns, teen smoking cessation programmes, social environment changes, community interventions, and increasing cigarette prices. A significant proportion of the resources obtained from the recent settlement between 46 US states and the tobacco industry should be devoted to expanding, improving and evaluating "youth centred" tobacco prevention and control activities.