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.

Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin.

Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

[Complex regional pain syndrome (CRPS I) in hand surgery--misfortune of fate or avoidable? The viewpoint of a hand surgeon with many years of experience in this problem]. / Das komplexe regionale Schmerzsyndrom (CRPS I) in der Handchirurgie--schicksalshaft oder vermeidbar? Sichtweise eines Handchirurgen mit jahrzehntelanger Erfahrung mit dem Problem.

The complex regional pain syndrome type I (CRPS I) is a complication of the healing process of the whole body, not solely a part of it (e. g., the hand), which is caused by a multiplicity of factors. My conviction that the CRPS should less be considered as a misfortune of fate but rather can be avoided in the majority of cases is based on my experience from the last 25 years. The most important prognostic factor is the time period between the first symptoms and the beginning of the therapy.

Chemokine IP-10: an adjunct marker for latent tuberculosis infection in children.

SETTING: Recent reports indicate a role of chemokine inducible protein 10 (IP-10) in Mycobacterium tuberculosis infection substantiated by the detection of elevated levels in plasma and at infection foci in individuals infected with M. tuberculosis. OBJECTIVE: To evaluate IP-10 as a potential marker for the diagnosis of M. tuberculosis infection in children living in a region of low tuberculosis (TB) prevalence. DESIGN: IP-10 levels were obtained after whole blood stimulation with M. tuberculosis-specific antigens in 127 children. IP-10 results were evaluated upon gradations of exposure risk to M. tuberculosis and correlation with tuberculin skin test and an interferon-gamma release assay (IGRA). RESULTS: IP-10 reactivity correlated well to risk of exposure to M. tuberculosis in children. There was a strong correlation between IP-10 and IGRA results. IP-10 responses, unlike interferon-gamma (IFN-gamma), were not age-dependent and detected more positive results in children aged <5 years. In the children with active disease, the IGRA was more sensitive than IP-10 at detecting M. tuberculosis infection. CONCLUSION: Our findings suggest that IP-10 in combination with IFN-gamma may enhance the diagnostic performance of IGRAs in detecting M. tuberculosis infection, especially in young children.

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.

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.

Pneumocystis carinii infection presenting as an intra-abdominal cystic mass in a child with acquired immunodeficiency syndrome.

We describe the case of a pediatric patient with acquired immunodeficiency syndrome (AIDS) with an unusual large, fluid-filled intra-abdominal cystic lesion in which Pneumocystis carinii trophozoites were identified. Extrapulmonary P. carinii infection should be considered in the differential diagnosis of an intra-abdominal cystic mass in a child with AIDS.

Prevalence of the T215Y mutation in human immunodeficiency virus type 1-infected pregnant women in a New York cohort, 1995--1999.

From 1997 through 1999, the prevalence of the zidovudine resistance mutation T215Y was 9.7% among pregnant women, and the human immunodeficiency virus type 1 (HIV-1) load in those with resistant virus was higher than that measured in women with wild-type HIV-1. All mutations were noted in women with zidovudine experience, which suggests that monotherapy may not be adequate prophylaxis for vertical transmission of HIV-1 infection in the current era.

Asbestos causes apoptosis in alveolar epithelial cells: role of iron-induced free radicals.

Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-induced reactive oxygen species (ROS) is one important mechanism. To determine whether asbestos causes apoptosis in AECs, we exposed WI-26 (human type I-like cells), A549 (human type II-like cells), and rat alveolar type II cells to amosite asbestos and assessed apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine-5'-triphosphate-biotin nick end labeling (TUNEL) staining, nuclear morphology, annexin V staining, DNA nucleosome formation, and caspase 3 activation. In contrast to control medium and TiO2, amosite asbestos and H2O2 each caused AEC apoptosis. A role for iron-catalyzed ROS was suggested by the finding that asbestos-induced AEC apoptosis and caspase 3 activation were each attenuated by either an iron chelator (phytic acid and deferoxamine) or a.OH scavenger (dimethyl-thiourea, salicylate, and sodium benzoate) but not by iron-loaded phytic acid. To determine whether asbestos causes apoptosis in vivo, rats received a single intratracheal instillation of amosite (5 mg) or normal saline solution, and apoptosis in epithelial cells in the bronchoalveolar duct regions was assessed by TUNEL staining. One week after exposure, amosite asbestos caused a 3-fold increase in the percentage of apoptotic cells in the bronchoalveolar duct regions as compared with control (control, 2.1% +/- 0.35%; asbestos, 7.61% +/- 0.15%; n = 3). However, by 4 weeks the number of apoptotic cells was similar to control. We conclude that asbestos-induced pulmonary toxicity may partly be caused by apoptosis in the lung epithelium that is mediated by iron-catalyzed ROS and caspase 3 activation.

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.

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.

Translating behavioral health services research into benefits policy.

This article uses a 4-pronged statistical approach to examine the impact of a mental health carve-out at a major employer. To examine net financial impact of the carve-out, the authors perform a pre-post, multivariate regression analysis of changes in costs. Using a random-effects model, the authors explore the ultimate financial impact of the carve-out for patients and for the firm. Using a multinomial logistic regression, they examine differing program effects by intensity of use. A fixed-effects negative binomial regression models the episodic nature of outpatient care, controlling for patient-specific unobserved characteristics that influence health care utilization. The carve-out slightly reduced overall mental health costs and utilization while expanding entry-level access to routine services. At the same time, the specific carve-out shifted financial burdens from the firm onto high-utilization patients. Therefore, this carve-out appears poorly suited to the care of individuals experiencing severe and debilitating psychiatric disorders.

Nutrition-related cardiovascular risk factors in older people: results from the Third National Health and Nutrition Examination Survey.

SETTING: In view of the recognized potential benefits of nutritional therapy in older persons, Congress is evaluating the coverage of nutritional services for Medicare beneficiaries. OBJECTIVE: To estimate the number of older persons in the US who have one or more cardiovascular risk factors (hypertension, increased low density lipoprotein (LDL) cholesterol, and diabetes mellitus), for which nutritional therapy is recommended. DESIGN: Cross-sectional analysis of adults, aged > or = 65, participating in the Third National Health and Nutrition Examination Survey (NHANES III). MAIN OUTCOMES: The authors estimated the proportion of adults, aged > or = 65, with diabetes mellitus, increased LDL cholesterol, and/or hypertension. Efforts were made to assess whether obesity status, gender, race, and/or socioeconomic factors were associated with the prevalence of any or all three conditions. RESULTS: Approximately 86% (20 million persons) in the US, aged > or = 65, have at least one of the index conditions. Whereas a higher body mass index (BMI) increased the likelihood of having any or all three conditions, 81% of persons of average body weight (BMI <25 kg/m2) had at least one condition. After adjusting for age, gender, BMI, marital status, and poverty index, blacks were more likely than whites to have any one condition (odds ratio (OR) = 3.0, P < .01) or all three conditions (OR = 2.3, P = .05). CONCLUSIONS: Almost 90% of Americans aged > or = 65 have one or more nutrition-related cardiovascular risk factors. Improved nutritional interventions may be valuable especially for blacks, who have a higher prevalence of conditions requiring nutritional therapy.

Welfare reform, substance use, and mental health.

Reform has transformed traditional entitlement to cash welfare under Aid to Families with Dependent Children (AFDC) into a transitional program known as Temporary Assistance to Needy Families (TANF). Because of the new work requirements and the time-limited nature of assistance, policy makers are increasingly confronted with what to do when welfare recipients do not effectively make the transition from welfare to work. Increasingly, the language of public health is being used to determine who is "employable" and who is not. Thus renewed attention is being focused on the individual characteristics of participants themselves, particularly specific diagnoses that might reduce employability. This article focuses on substance abuse and mental health problems among single mothers and examines their relationship to welfare receipt. We analyze data from the 1994 and 1995 National Household Survey of Drug Abuse (NHSDA) and find that 19 percent of welfare recipients meet the criteria for a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, third edition revised) psychiatric diagnosis. About the same percentage have used illicit drugs during the previous year. Logistic regression results indicate that mental and behavioral health problems that are significant barriers to self-sufficiency are increasingly important in this era of time-limited benefits.

The impact of early initiation of highly active antiretroviral therapy on the human immunodeficiency virus type 1-specific CD8 T cell response in children.

This cross-sectional study investigated the effect of early highly active antiretroviral therapy (HAART) on human immunodeficiency virus (HIV) type 1-specific CD8 T cell responses in children. HIV-1-specific CD8 T cell responses were quantified using an enzyme-linked immunospot assay to measure interferon-gamma-secreting cells. HIV-1-infected children were classified by time of HAART initiation prior to age 1 year or after age 2 years as early (n=24) or late (n=28) treated. The magnitude and breadth of the HIV-1-specific CD8 T cell response was significantly lower in children receiving early compared with late HAART treatment (P=.0007 and.0001, respectively). However, total CD8 T cell responses in the early HAART treatment group did not differ significantly from those of age-matched non-HAART-treated controls (n=30). Thus, the reduced magnitude and breadth of the HIV-1-specific CD8 T cell response in early HAART-treated children is due to their younger age.

Maternal smoking and adverse birth outcomes among singletons and twins.

OBJECTIVES: This study assessed the effects of maternal smoking on birth outcomes among singletons and twins. METHODS: An algorithm was developed to link twins with their siblings in the 1995 Perinatal Mortality Data Set. A random-effects logistic regression model was then used to estimate the association between maternal smoking and several adverse outcomes for a random sample of singletons and for all twins with available maternal smoking information. RESULTS: The algorithm successfully linked sibling pairs for 91% of the twin sample. Maternal smoking was associated with a significantly increased risk of low birthweight, very low birthweight, and gestation of less than 33 weeks for both singletons and twins and with an increased risk of gestation of less than 38 weeks, infant mortality, and placental abruption for singletons. Among smokers, negative impacts on the risk of low birthweight, very low birthweight, and extreme premature delivery were significantly higher for women carrying twins. CONCLUSIONS: Some of the negative effects of smoking on low birthweight and preterm delivery are greater for twins than for singletons. Women carrying twins should be warned that smoking increases their already high risk of serious infant health problems.