Osteopathic philosophy is consistent with an emphasis on primary care and suggests that osteopathic physicians may have distinctive ways of interacting with their patients.The National Ambulatory Medical Care Survey (NAMCS) was used to derive national estimates of utilization of osteopathic general and family medicine physicians during 2003 and 2004 and to examine the patient characteristics and physician-patient interactions of these osteopathic physicians. All analyses were performed using complex samples software to appropriately weigh outcomes according to the multistage probability sample design used in NAMCS and multivariate modeling was used to control for potential confounders.When weighted according to the multistage probability sample design used, the 6939 patient visits studied represented an estimated 341.4 million patient visits to general and family medicine specialists in the United States, including 64.9 million (19%) visits to osteopathic physicians and 276.5 million (81%) visits to allopathic physicians. Osteopathic physicians were a major source of care in the Northeast , providing more than one-third of general and family medicine patient visits in this geographic region. Pediatric and young adult patients , Hispanics , and non-Black racial minority groups  were less likely to visit osteopathic physicians. There were no significant differences between osteopathic and allopathic physicians with regard to the time spent with patients, provision of five common preventive medicine counseling services, or a focus on preventive care during office visits.Osteopathic physicians are a major source of general and family medicine care in the United States, particularly in the Northeast. However, pediatric and young adult patients, Hispanics, and non-Black racial minorities underutilize osteopathic physicians. There is little evidence to support a distinctive approach to physician-patient interactions among osteopathic physicians in general and family medicine, particularly with regard to time spent with patients and preventive medicine services. Osteopathic philosophy maintains that: 1) the body is a unit and the person is a unit of body, mind, and spirit; 2) the body is capable of self-regulation, self-healing, and health maintenance; 3) structure and function are reciprocally interrelated; and 4) rational treatment is based on an understanding of the basic principles of body unity, self-regulation, and the interrelationship of structure and function [ the body the body structur rationalSome claim that osteopathic physicians, because of their philosophy and orientation toward primary care, may interact with their patients in ways that are distinctive from other health care providers. This has been characterized as a holistic or patient-centered approach, with a focus on preventive care . In the The First Osteopathic Survey of Health Care in America (OSTEOSURV-I), a random national telephone survey, addressed patient satisfaction with various elements of health care provided by osteopathic physicians, allopathic physicians, chiropractors, and other non-physician clinicians . In OSTEInvestigators at Michigan State University College of Osteopathic Medicine (MSUCOM) conducted a random national mail survey of osteopathic physicians to identify philosophical and practical differences that they believed distinguished them from their allopathic counterparts . OsteopaWhile these cited studies provide some insight into osteopathic medicine and the physician-patient interactions characteristic of osteopathic primary care, they are limited in various ways. The MOOS study involved only 18 physicians and 54 patients in a geographically limited area; therefore, its findings may not be generalizable on a national level . AlthougThe concept of the National Ambulatory Medical Care Survey (NAMCS) to collect data on medical care provided in physician offices in the United States was developed over 30 years ago . DocumenThe first stage included 112 PSUs, which consisted of counties, groups of counties, county equivalents (e.g. parishes), towns, townships, minor civil divisions, or metropolitan statistical areas (MSAs). These PSUs comprised a probability subsample of those used in the 1985–1994 National Health Interview Surveys . The latThe second stage consisted of a probability sample of practicing physicians selected from the master files of the AOA and the American Medical Association (AMA). Within each PSU, all eligible physicians were stratified by specialty: general and family practice, internal medicine, pediatrics, general surgery, obstetrics and gynecology, orthopedic surgery, cardiovascular diseases, dermatology, urology, psychiatry, neurology, ophthalmology, otolaryngology, and all other specialties. A separate specialty designation was provided for osteopathic physicians.The third stage involved selection of patient visits within the practices of participating physicians. Initially, the physician was randomly assigned to one of the 52 weeks within the calendar year. Then, a systematic random sample of patient visits was selected by the physician during the assigned week. The sampling rate of patient visits varied from a 20% sample for very large practices to 100% for very small practices as determined by a presurvey interview . In thisThe sampling frame for NAMCS included all physicians in the master files of the AOA and AMA prior to the start of the survey year who met the following criteria: (1) office-based; (2) principally engaged in patient care activities; (3) nonfederally employed; and (4) not in the specialties of anesthesiology, pathology, or radiology. During 2003 and 2004, a total of 6000 physicians, including 460 (8%) osteopathic physicians and 5540 (92%) allopathic physicians, were initially screened. Of these, 2032 (34%) did not meet the four criteria listed above and were ineligible. The most common reasons for being ineligible were that the physician was retired, deceased, or employed in teaching, research, or administration. Of the remaining 3968 eligible physicians, 2779 (70%) participated in NAMCS. Among the participating physicians, 544 (20%) saw no patients during their assigned reporting period because of vacations, illness, or other reasons for being temporarily not in practice.The basic sampling unit for NAMCS is the physician-patient encounter or "visit." The following types of contacts were excluded: telephone calls, visits outside the physician's office , visits made in hospital settings , visits made in institutional settings that had primary responsibility for the patient's care , and visits to the physician's office for administrative purposes only .Data for NAMCS were collected by the physician with assistance from office staff when possible. Patient record forms were used to collect the data for each selected visit. The NAMCS field staff performed completeness checks of the patient record forms prior to submission for central data processing. Detailed editing instructions were provided to reclassify or recode ambiguous or inconsistent data entries. Quality control measures, which were used to verify the accuracy of computer data entry, indicated that the mean keying error rate was 0.1% for nonmedical items and that discrepancy rates ranged from 0.0% to 1.1% for required medical items.Item nonresponse rates were 5% or less for most variables. Major exceptions (nonresponse rate) included: ethnicity (20%), race (18%), tobacco use (30%), and time spent with physician (16%). Missing data for birth year (4%), sex (4%), race (18%), ethnicity (20%), and time spent with physician (16%) were imputed by assigning the value from a randomly selected patient record form representing another patient with similar known characteristics. Such imputations were performed according to physician specialty, geographic region (state was used instead of geographic region to impute ethnicity), and primary diagnosis codes.Each record in the NAMCS data file was assigned a patient visit weight based on four factors: (1) probability of being selected by the three-stage sampling design; (2) adjustment for nonresponse; (3) adjustment for physician specialty group; and (4) weight smoothing to minimize the impact of a few physician outliers whose final visit weights were large relative to those for the remaining physicians. Thus, by applying the relevant patient visit weights to each of the 50,574 records in the 2003 and 2004 NAMCS data files, an estimated 1.82 billion physician office visits in the United States were represented. When weighted according to the multistage probability sample design, the NAMCS data may be used to derive unbiased national estimates of ambulatory medical care services utilization and to further characterize such services.The electronic files containing the 2003 and 2004 NAMCS data were acquired from the National Center for Health Statistics. The files were merged and analyzed using SPSS Version 14.0 for Windows . Because the multistage probability design of NAMCS includes clustering, stratification, and the assignment of unequal probabilities of selection to sample units, all analyses were performed with the SPSS complex samples module to accurately compute estimates of population parameters and their standard errors . The preThe primary variables of interest included patient characteristics, place of residence, episode of care , major reason for the physician office visit , length of time spent with patient, and five common patient counseling services . The time spent with patients and provision of each of these five types of patient counseling was used to assess physician-patient interactions.National estimates of the use of osteopathic and allopathic physicians in the specialty of general and family medicine were derived. Multiple logistic regression was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the use of osteopathic physicians, controlling for potential confounders, including patient characteristics, place of residence, episode of care, and major reason for the physician office visit. Additionally, the osteopathic population attributable percentage (PAP) was used to express the percentage of national office visits provided by osteopathic physicians.The time spent with patients by osteopathic and allopathic physicians was compared using a multiple linear regression model that controlled for the potential confounders delineated above. This model was used to compute adjusted means and standard errors of time spent with patients according to physician provider type and levels of each potential confounder. National estimates of the provision of diet or nutrition counseling, weight reduction counseling, exercise counseling, tobacco use or exposure counseling, and mental health or stress reduction counseling were also derived. The provision of these counseling services by osteopathic and allopathic physicians was compared using multiple logistic regression to compute adjusted ORs and 95% CIs that controlled for the potential confounders listed above. All hypotheses were tested at the .05 level of statistical significance.There were an estimated 341.4 million patient visits to general and family medicine specialists during 2003 and 2004, including 64.9 million (19%) visits to osteopathic physicians and 276.5 million (81%) visits to allopathic physicians. The patient and visit characteristics according to physician provider type are presented in Table The adjusted national estimates of time spent with physician during general and family medicine patient visits are presented in Table The national estimates of patient counseling during the 341.4 million general and family medicine patient visits studied were as follows: diet or nutrition counseling, 65.4 million (19%); weight reduction counseling, 17.0 million (5%); exercise counseling, 45.7 million (13%); tobacco use or exposure counseling, 13.7 million (4%); and mental health or stress reduction counseling, 19.6 million (6%).The patient and visit characteristics associated with the provision of diet or nutrition counseling, weight reduction counseling, and exercise counseling are presented in Tables The patient and visit characteristics associated with the provision of tobacco use or exposure counseling, and mental health or stress reduction counseling, are presented in Tables The results of this study involving a large nationally representative sample of office visits provides a clearer picture of the characteristics of patients visiting osteopathic physicians in general and family medicine, and of the physician-patient interactions occurring during such visits. Overall, there were an estimated 64.9 million ambulatory visits to osteopathic physicians in general and family medicine during 2003 and 2004. Osteopathic physicians accounted for about one-fifth of general and family medicine visits in the United States during this period.Osteopathic medicine was founded in and has traditionally been most strongly associated with the Midwest . The finThis study also extends previous findings with regard to use of osteopathic physicians in racial or ethnic minority groups  by identThis study found little evidence to support a distinctive approach to physician-patient interactions among osteopathic physicians in general and family medicine. Patients spent comparable amounts of time with osteopathic and allopathic physicians during office visits, even after controlling for patient characteristics, place of residence, episode of care, and reason for the visit. There were no significant differences between osteopathic and allopathic physicians with regard to the provision of five common types of counseling within the realm of preventive medicine. Finally, there was no evidence that patients visited osteopathic physicians for preventive care more often than they visited allopathic physicians for such care.Certainly, there are other elements of the physician-patient interaction that were not captured with the NAMCS patient record form used during office visits. However, the primary variables studied herein – time spent with patients, provision of common preventive medicine counseling services, and a focus on preventive care during office visits – represent aspects of medical care commonly emphasized as manifestations of the osteopathic philosophy. Failure to identify distinctive patterns of care rendered by osteopathic general and family medicine physicians in any of these primary variables brings into question the existence of a unique osteopathic approach to medical care. Further, although not directly measured in NAMCS, the use of OMT during office visits may have been infrequent based on the comparable amount of time spent with patients by osteopathic and allopathic physicians. One obvious factor that may have impacted the study results, attenuating differences between osteopathic and allopathic physicians, is the training of osteopathic physicians in ACGME-accredited residency programs. As such training is generally on the rise ,4,20, itThere are several potential limitations of this study. First, with regard to information, NAMCS data were collected by the physician providers with assistance from their office staff rather than by independent survey personnel. Thus, there exists the potential for variability in the data collection process across physician providers, potentially leading to imprecision or information bias in the reported data. For example, a very brief mention of nutrition and a much more comprehensive counseling session on diet both may have met the criterion of diet or nutrition counseling during a patient visit. However, the relatively low percentages of patient visits during which the various types of counseling were reported to have occurred suggest that physician overreporting was not an important source of bias.Second, with regard to provision of patient counseling, the implicit assumptions were that patients of osteopathic and allopathic physicians were comparable in their need for counseling and that more frequent counseling was indicative of more optimal physician-patient interactions. However, in 2003 and 2004, NAMCS did not routinely collect patient data to adequately assess the need for most of the counseling services studied and to thereby verify these assumptions. Beginning in 2005, the NAMCS patient record form routinely collects data on patient height and weight, thereby enabling future investigators to more adequately control for the need of counseling in such areas as diet or nutrition, weight reduction, and exercise.Third, there were substantial amounts of missing data for ethnicity, race, and time spent with physician. Although these missing values were imputed by NAMCS personnel using accepted statistical methods, the imputed data cannot be validated with absolute certainty.Finally, the selection of physicians and their patients should also be addressed. Overall, 70% of eligible physicians elected to participate in the survey. Among participating physicians, one-fifth saw no patients during their assigned reporting period for various reasons. Thus, some degree of selection bias in NAMCS cannot be ruled out. Further, the findings of this study apply only to general and family medicine physicians and cannot be extrapolated to other specialty physicians, including those in other primary care specialties.Osteopathic physicians are a major source of general and family medicine care in the United States, particularly in the Northeast. However, pediatric and young adult patients, Hispanics, and non-Black racial minorities underutilize osteopathic physicians across the nation. There is little evidence to support a distinctive approach to physician-patient interactions among osteopathic physicians in general and family medicine, particularly with regard to time spent with patients and preventive medicine services.Osteopathic Medicine and Primary Care. He was not involved in the review of the manuscript or in the editorial decision with regard to its suitability for publication.JCL is Editor-in-Chief of


Every day, Earth-observing satellites outfitted with remote-sensing technology generate vast data streams that scientists use to study the biosphere—the part of the Earth and its atmosphere that can support life. These orbiting systems are rapidly advancing studies of climate change, weather, and other global phenomena. Now experts are looking for ways to put them to work in the field of environmental health research.Recently, the NIEHS and the U.S. Environmental Protection Agency (EPA) united health and Earth scientists in a workshop charged with two key objectives. The first was to determine if observations of air quality and climate from space could be used as public health tools for research, policy decisions, and environmental and health planning. The second was to engage the NIEHS extramural research community in dialogue with remote-sensing data producers and organizers including the National Oceanic and Atmospheric Administration, the National Aeronautics and Space Administration, and the EPA. Together these experts explored ways to use Earth observation data in studies of air pollution and health.The workshop, titled “Global Earth Observations: Application to Air Quality and Health,” was held at the NIEHS campus on 1–2 August 2005, and was attended by several dozen academic and government scientists. “Health researchers already use ground-based measurements of air pollution [to assess human exposures], and the workshop provided a mechanism for them to consider if addition of remote-sensed data would improve their exposure assessment and analysis of disease outcomes,” says Sally Tinkle, a program administrator with the Cellular, Organs, and Systems Pathobiology Branch of the NIEHS Division of Extramural Research and Training. Tinkle, together with NIEHS program analysts Mary Gant and Mike Humble and EPA representatives Gary Foley, Valerie Garcia, and Andy Bond, organized the event and provided NIEHS scientific support.The NIEHS plays a growing role in the use of this technology, in part through its membership in the U.S. Group on Earth Observations (USGEO), a standing committee that reports to the National Science and Technology Council’s Committee on Environment and Natural Resources. The USGEO recently drafted a 10-year strategic plan for applying Earth observations to health and environmental research, which was released by the White House on 6 April 2005. Tinkle is the NIEHS’s USGEO representative, and Gant leads the USGEO’s User Interface Working Group.At the August workshop, speakers covered issues ranging from the strength and adequacy of remote-sensing data to new directions in satellite research, coverage with land-based monitoring networks, and the challenges of using spatial data to address air quality and health outcomes. Participants also split into working groups to identify potential demonstration projects for remote sensing in three areas of health research: respiratory disease, cardiovascular disease, and developmental biology. Outcomes in all three areas have been linked to air pollution.Despite an initial focus on user needs in the area of remote-sensing data architecture—the way data are organized, stored, and made available to users—the workshop dialogue shifted frequently to feasibility issues. While the health scientists present found the technology intriguing, they raised questions about its potential for human exposure assessment.Resolution limits were of particular concern. Remote sensing’s spatial resolution, for instance, is rarely less than a square kilometer, although there is increasing evidence that air pollution levels vary at much finer scales of resolution . Temporal resolution can also be problematic, especially for polar-orbiting satellites, whose positions remain fixed as the Earth rotates beneath them .Discussions also addressed methods for averaging pollution concentrations measured from space. Remote sensors measure pollution in atmospheric columns that extend to the outer edge of the stratosphere. Humans, however, are exposed to pollutants close to the Earth’s surface.Finally, participants discussed limits on remote particulate measurements, which don’t extend below the 10-micron level and cannot distinguish between chemical species on particle surfaces. “All these factors contribute to the uncertainty of linking remote-sensing data to human effects,” says workshop participant Raymond Hoff, a professor of physics at The University of Maryland, Baltimore County.According to Tinkle, feasibility discussions exposed the need for demonstration studies that layer remote-sensing data over existing ground-based pollution data sets. “This would permit us to determine if the addition of remote-sensing data improves the correlation of air pollution with adverse health events—such as asthma exacerbation and myocardial arrhythmias, for instance—in the area of respiratory and cardiovascular disease,” she says.Peggy Reynolds, an investigator with the Environmental Health Investigations Branch of the California Department of Health Services, moderated the working group on respiratory disease. During breakout sessions, participants identified key data needs in this area. They included improved measures for data quality assurance and control, validated correlations with health outcomes, and confirmation that remote-sensing data accurately represent exposures on the ground. Participants speculated that remote sensing could help fill gaps in existing exposure data and suggested a demonstration project that correlates asthma prevalence with remote-sensed measures of airborne particulates and bioallergens.Diane Gold, an associate professor at the Harvard University School of Public Health, moderated the cardiovascular disease working group. Participants in this group identified “applications,” or health outcomes, that might be served by remote-sensing data. Among them were myocardial infarction, arrhythmia, heart failure, hypertension, and stroke, in addition to a number of subclinical outcomes such as blood pressure changes and heart rate variability. Population-level application areas were also identified; they included hospital admissions and emergency room visits. Participants concluded that resolution limits might not pose problems for chronic applications, but that acute events like myocardial infarction and stroke would be better served by higher-resolution technology.The developmental biology working group, moderated by Beate Ritz, an associate professor of epidemiology at the University of California, Los Angeles, identified several uses of remote-sensing data to assess developmental outcomes; they included critical windows of vulnerability that occur before, during, and following parturition; acute versus chronic pollutant exposure dynamics; and the interaction of maternal and fetal genetic susceptibilities. Participants also identified data needs such as adequate temporal and spatial resolution in pollution measures, and improved identification and quantification of chemical species in air pollution.The workshop prompted Earth and health scientists to begin a dialogue to develop web-based pilot studies that integrate existing remote-sensing data with ground-based analyses as a preliminary step toward this broader validation. The workshop generated significant enthusiasm for collaboration between NIEHS extramural researchers and scientists at the participating agencies and for the possible use of remote-sensing air quality and climate data to improve public health. Ideally, space-based measures will produce new views of air pollution and the extent of human exposure, possibly leading to better opportunities to protect public health.


Acris crepitans) collected in Illinois and deposited in museum collections to elucidate relationships between the decline of this species in Illinois and the spatial and temporal distribution of individuals with intersex gonads. Compared with the preorganochlorine era studied (1852–1929), the percentage of intersex cricket frogs increased during the period of industrial growth and initial uses of polychlorinated biphenyls (PCBs) (1930–1945), was highest during the greatest manufacture and use of p,p-dichlorodiphenyltrichloroethane (DDT) and PCBs (1946–1959), began declining with the increase in public concern and environmental regulations that reduced and then prevented sales of DDT in the United States (1960–1979), and continued to decline through the period of gradual reductions in environmental residues of organochlorine pesticides and PCBs in the midwestern United States (1980–2001). The proportion of intersex individuals among those frogs was highest in the heavily industrialized and urbanized northeastern portion of Illinois, intermediate in the intensively farmed central and northwestern areas, and lowest in the less intensively managed and ecologically more diverse southern part of the state. Records of deposits of cricket frog specimens into museum collections indicate a marked reduction in numbers from northeastern Illinois in recent decades. These findings are consistent with the hypothesis that endocrine disruption contributed to the decline of cricket frogs in Illinois.Exposure to anthropogenic endocrine disruptors has been listed as one of several potential causes of amphibian declines in recent years. We examined gonads of 814 cricket frogs ( Acris crepitans, the causes of declines are unclear. This species is indigenous to the eastern half of the United States and has experienced a marked decline in portions of its range in the last 25 years  may produce estrogenic, antiestrogenic, and antiandrogenic effects , polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo- effects . For exa scripta , various scripta , and fis scripta . Moreove scripta . In addi scripta .p,p-dichlorodiphenyl-trichloroethane (DDT) and its metabolites/ environmental products have demasculinized birds , reptiles (Alligator mississippiensis), and fish (Xenopus laevis) and slider turtles (T. scripta), and the organochlorine insecticides toxaphene and dieldrin induced this protein in male X. laevis (Hyla versicolor) and increased time to metamorphosis in X. laevis  a preorganochlorine period (1852–1929); b) an era of PCB use and industrialization that predates use of DDT (1930–1945); c) a period of rapidly increasing DDT use and further industrialization (1946–1959); d ) a period of declining use and then a ban on sales of DDT as well as initial measures to limit pollution from industries (1960–1979); and e) a period associated with a substantial decline in environmental residues of organochlorine insecticides and other persistent halogenated organic air and water pollutants in the Midwest (1980–2001).Museum specimens from throughout Illinois  were exain situ with a dissecting microscope to identify sex. Because there is no evidence that testicular tissue develops within the female tract, females were identified by the presence of oocytes and excluded from further analysis. Testes, intersex gonads, and poorly differentiated gonads were removed for histologic examination. When museums limited the proportion of cricket frogs from which gonads could be taken, we used a random numbers table to select a subset for histologic study. Collection dates, collecting localities, and notes from museum catalogs were recorded. Gonads were immersed in 70% ethanol, embedded in paraffin, and sectioned at 5 μm. Depending on gonad size, longitudinal sections were obtained beginning 60–150 μm from the outer edge. Two or three sections 60–120 μm apart were selected for processing. Slides were stained with hematoxylin and eosin and examined with a light microscope for the presence of sperm production and oocytes. When oocytes were present within testicular tissue, they were relatively few in number, but each was several-fold larger than the spermatic ducts and thus took up a substantial percentage of testicular volume, making them easy to identify.The gonads of 814 cricket frogs were examined We used Systat 10.2  to construct contingency tables and perform Pearson chi-square analyses comparing proportions of male, female, and intersex individuals among the five time periods and three areas of Illinois. Further analysis incorporating temporal and spatial dimensions simultaneously was not possible because of the limited numbers of intersex specimens at some time points. Specifically, tables based on all five time periods and three regions broken down by sex would have included cells with no data. The null hypotheses tested whether the proportion of male, intersex, and female frogs is the same for frogs captured during the five time periods and in the three areas of the state. We used the 5% significance level as the indicator of a statistically significant association.A. crepitans, the frog species most often collected in Illinois. Years of collection ranged from 1852 to 2001. A trend of increasing numbers of frogs collected started in the late 1930s; there was a marked reduction during World War II, and then the rate of collecting markedly increased through the mid-1950s. Numbers of individual anurans collected declined sharply in the late 1950s, increased during the mid-1960s, and declined during the 1970s and 1980s. The numbers of frogs collected in Illinois have since increased. Cricket frog numbers were largely proportional to those of other anurans  were  anurans . Other f anurans . Moreove anurans .n = 37) had an ovotestis where proportionately large ova were present within testicular tissue, and a few (n = 6) had a complete testis and complete ovary. The proportions of specimens in each gonadal sex class differed significantly among the geographical regions in Illinois  was manifested in two forms: most intersex frogs  to p,p-DDE  stimulated growth of Mullerian ducts consistent with estrogenicity, exposure to technical-grade DDT had a paradoxical antiestrogenic effect  and the decline of cricket frogs were congruent. The observed decline was evident after a period of sustained endocrine disruption, as indicated by a large increase in prevalence of intersex gonads and masculinization of the population. A plausible explanation for these observations is that exposures to antiestrogenic PAHs, PCBs, PCDFs, PCDDs, and DDT caused endocrine disruption, and this contributed to the virtual disappearance of cricket frogs from the Chicago region. The intersex prevalence in cricket frogs in recent years is low and may represent a near-baseline condition. A suite of endocrine-disrupting organochlorine contaminants persists in soils and waters of the Midwest, but at substantially reduced levels compared with earlier decades . However


Real life prescription of these drugs may be substantially different than that considered in pharmacoeconomic analyses or claimed by drug companies, yet. Our objective was to evaluate whether coxibs were associated with reduced prescription of gastro-protective agents . Logistic regression was used to calculate the odds ratio of GPA prescription for coxib and non-selective NSAID adult users (> 14 years). Three categories of users were further investigated: "acute", "chronic and "incident or new". Main outcome measures were same-day co-prescription and 30 days prescription of GPAs in coxibs and non selective NSAIDs users. To limit selection bias, data were adjusted for age, sex, DDD of coxibs and non selective NSAIDs received during 2001, DDD of GPAs and (for non-incident users) DDD of NSAIDs received during the previous 4 yearsSame day co-prescription rates were similar considering the overall population and "acute" users. Chronic coxibs users instead showed higher co-prescription rates than chronic NSAIDs users . GPA prescription within thirty days was also higher among all subgroups of coxibs users .Assumptions made in pharmacoeconomic analyses on coxibs (lower GPA prescription associated with coxibs use) may be overly optimistic. Claims made through cost-effectiveness data should be carefully interpreted, and mechanisms for attributing drug prices revised accordingly. Pharmacoeconomic analyses are used to highlight potential advantages of new drugs over older ones by showing, in general, that higher effectiveness and/or less frequent side effects may be worth the  higher cost. Assumptions and findings from these analyses may not reflect everyday practice yet, as real life prescription and use of marketed drugs may be different from that observed in Randomised Controlled Trials and/or assumed in economic models.Coxibs were found to have higher gastrointestinal tolerability than traditional NSAIDs, but their overall safety profile is controversial in light of cardiovascular risks demonstrated for rofecoxib, celecoxib and  for parecoxib and valdecoxib -5. TheseIn Italy, the co-prescription of GPAs and coxibs is theoretically not allowed, since GPAs prescription should be justified – on the prescription itself – on clinical grounds other than the use of a coxib. Often in practice, doctors do not follow this rule and co-prescribe GPAs with coxibs. Our purpose was to explore whether coxibs are associated with (at least)reduced co-prescription rates of GPAs in comparison with traditional NSAIDs, thus testing one of the main assumptions of pharmacoeconomic analyses on these drugs.2 blockers and misoprostol), occurring either the same day of, or within 30 days since (assumed as an adequate time window for acute gastrotoxic events), prescription of oral NSAIDs and/or coxibs. Information about time and amount of prescribing, and age and sex of recipients were collected. All these prescriptions are free of charge within our Regional Health System.We performed a record-linkage study using 2001 NHS prescription data from an electronic database of outpatient prescriptions of the province of Modena . Specifically, we analysed prescriptions of GPAs . Specific subgroups were investigated: "acute" users, defined as those who received less than 60 Defined Daily Doses (DDD) of traditional NSAIDs or coxibs during 2001; "chronic" users, as those who received at least 60 DDD of any anti-inflammatory drug during 2001 (96% of them had received at least a two-pieces repeated prescription over four months); "incident"/new users, as those who had never been prescribed any NSAIDs during the previous four years; in this latter group, we further distinguished those who had never been prescribed GPAs in the same period . In addition to considering those subgroups, further attention was given to limit selection bias (prescription of coxibs to patients at higher risk of GI bleeding) by adjusting for age, sex, DDD of coxibs and non selective NSAIDs received during 2001, DDD of GPAs and [*] (for non-incident users) DDD of NSAIDs received during the previous 4 years.In 2001, coxibs and oral non-selective NSAIDs were prescribed to 3.4% and 9.2% of the adult population of the study area, respectively. The vast majority of patients treated with these drugs (73.5%) were acute users ; almost no difference existed in the proportion of coxibs and non-selective NSAIDs acute users. About 50% of coxibs and NSAIDs users were "incident" users (subjects having not received any NSAIDs in the previous four years).2 receptor antagonists and misoprostol, respectively (some patients have taken different classes of GPAs at different times). Table GPAs were co-prescribed to 6.1% of individuals receiving anti-inflammatory drugs, and 5.7% were prescribed GPAs within 30 days , our example suggests that coxibs may not be associated with reduced prescription of GPAs – as manufacturers claim or imply – and that preventive (and selective) co-prescription of GPAs and coxibs to those at higher risk of bleeding is not necessarily the key to the whole story. Unexpectedly, patients who received coxibs  were more "at risk" to be prescribed GPAs within 30 days. Moreover incident NSAIDs users, supposed to be less at risk of being prescribed GPAs (thus being less affected by selection bias), were actually co-prescribed GPAs more often the same day. This could mean that they are either not safer than traditional NSAIDs  or that anyway prescribers do not reduce co-prescription of GPA. Although gastrointestinal tolerability of coxibs is controversial, both RCT and observational studies exclude that coxibs are more gastrotoxic . On the plus GPAs, even if in Italy this represents an unlicensed use, and despite lacking evidence from RCTs on the higher safety profile of this combination compared to coxib alone or to traditional NSAIDs plus GPAs. In this regard, no evidence-based guideline recommends such a combination as a therapeutic alternative to NSAIDs/GPA combination. In actual practice, doctors may also be influenced by patients and especially drug representatives [Is it true that more expensive drugs eventually lower prescription costs? Such an assumption is often made in pharmacoeconomic analyses and has also been made in economic analysis on coxibs. The purpose of our study was to explore this assumption and our data, consistent with those of previous researches ,13  their work.GF coordinated study design, coordinated and did the statistical analysis, wrote the initial draft of the paper and revised the final version.AM participated in study design, extracted the data, coordinated and did the statistical analysisCV participated in study design, extracted the data and did the statistical analysisAV extracted the data, did the statistical analysis and revised the final versionNM had the original idea, coordinated study design and revised the final version;The article was read and approved by all contributors.


Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis. Cervical cancer remains one of the greatest killers of women worldwide. According to Globocan 2000, it is estimated that in 2000 the numbers of patients diagnosed with and those who died from this disease were 470,606 and 233,372, respectively . It is rCervical cancer is currently staged clinically according the International Federation of Gynecology and Obststrics (FIGO) guidelines. In terms of treatment, invasive disease can be divided into three main groups: 1) early stage going from microinvasive disease IA1, IA2 to macroscopic disease confined to cervix and measuring <4 cm, IB1; 2) locally advanced FIGO stages IB2-IVA, and 3) IVB and recurrent disease  and zebularine [272] as well as HDAC inhibitors including SAHA, M344, depsipeptide [273], and valproic acid [274] are radiosensitizers. In addition, it is very noteworthy that HDAC inhibitors such as phenylbutyrate, trichostatin A, and valproic acid are able to reduce cutaneous radiation toxicity following radiotherapy [275]. Therefore, radiation or chemoradiation in combination with DNA demethylating agents and/or HDAC inhibitors is a research avenue to be explored. Based on these data, a phase II study of transcriptional therapy with the demethylating hydralazine plus the histone deacetylase inhibitor magnesium valproate added to chemoradiation with cisplatin is ongoing in FIGO stage IIIB cervical carcinoma.Epigenetic alterations are at least if not more important than genetic defects for the development and progression of malignant diseases. In cervical cancer, a number of epigenetic alterations occurring during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes have been identified. These include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. From the diagnostic point of view, because epigenetic abnormalities occur very early in the carcinogenic process they can potentially be exploited as molecular markers for early detection. In this sense, identification of a set of genes hypermetylated in cytologic smears could offer novel means for screenning. Assessment of hypermethylated genes in primary tumor or in serum DNA may serve as a prognostic factor or as a means of predicting response to radiation, chemotherapy, and transcriptional agents.In the therapeutic field, transcriptional therapy is a very promising form of cancer treatment that is being extensively evaluated. It is too early to evaluate usefulness. However, it has now been demonstrated that inhibitors of DNA methylation and histone deacetylases can reactivate expression of tumor suppressor genes and induce hystone hyperacetylation in the tumors of patients with cervical cancer after treatment with these agents.AD-G conceived and wrote the manuscript; ML contributed with the HPV section; MC, LC, CA and EC participated in the discussion, analysis of the content.


A symposium on the mechanisms of action of inhaled airborne particulate matter (PM), pathogenic particles and fibers such as silica and asbestos, and nanomaterials, defined as synthetic particles or fibers less than 100 nm in diameter, was held on October 27 and 28, 2005, at the Environmental Protection Agency (EPA) Conference Center in Research Triangle Park, North Carolina. The meeting was the eighth in a series of transatlantic conferences first held in Penarth, Wales, at the Medical Research Council Pneumoconiosis Unit (1979), that have fostered long-standing collaborations between researchers in the fields of mineralogy, cell and molecular biology, pathology, toxicology, and environmental/occupational health.The goal of this meeting, which was largely supported by a conference grant from the NHLBI, was to assemble a group of clinical and basic research scientists who presented and discussed new data on the mechanistic effects of inhaled particulates on the onset and development of morbidity and mortality in the lung and cardiovascular system. Another outcome of the meeting was the elucidation of a number of host susceptibility factors implicated in adverse health effects associated with inhaled pathogenic particulates.New models and data presented supported the paradigm that both genetic and environmental  factors affect disease outcomes from inhaled particulates as well as cardiopulmonary responses. These future studies are encouraged to allow the design of appropriate strategies for prevention and treatment of particulate-associated morbidity and mortality, especially in susceptible populations. Inhaled durable particles and fibers (defined has having a greater than 3:1 length to diameter ratio) have been of concern to human health for over a century due to a myriad of publications reporting lung diseases in trade workers and miners prior to the enforcement of permissible exposure levels in the workplace. Although naturally occurring minerals such as asbestos and silica have been studied clinically and experimentally for many years, it is now clear that inhaled ambient particles also are associated with adverse health effects in man and animals, and their compositional components and biologic effects are now under intense investigation. Because synthetic nanomaterials often occur in size ranges similar to ultrafine airborne particles that are considered to be a major factor contributing to adverse health effects of air pollution, information on the biological reactivity of these particulates is also necessary to allow their safety evaluation.The goal of this symposium was to understand the mechanisms of action of inhaled particulate matter, known pathogenic minerals, and nanomaterials from presentation of data generated in a number of laboratories in academia, government, and industry. The thematic sessions included: 1) Airborne Particulate Matter-Cardiopulmonary Effects and Host Susceptibility Factors, 2) Metals and Metal Mixtures as Pathogenic Components of Particulate Matter, 3) Mechanisms of Asbestos-Induced Cell Injury and Remediation, 4) Occupational, Environmental and Genetic Factors in the Development of Disease by Fibrogenic Minerals and Cigarette Smoke, and 5) Nanoparticles and Nanomedicine. A recurrent theme throughout the conference was the role of oxidant stress and antioxidant status in response and host susceptibility to particle and fiber effects. Reactive oxygen species (ROS) production is only one of a number of signatures and repercussions of oxidant stress induced by inhaled particles and metals in cells and tissues. Information suggests that biomarkers of oxidative stress and therapeutic strategies targeting ROS and inflammation are ripe areas for prediction of risk and therapy of particle-induced diseases. This synopsis encompasses information presented at platform presentations, although a number of outstanding and relevant poster presentations were also featured at the meeting. We also reference recently published articles by investigators that were covered, in part or full, in their presentations.This synopsis encompasses information presented at platform presentations, although a number of outstanding and relevant poster presentations were also featured at the meeting. We also reference recently published articles by investigators that were covered, in part or full, in their presentations.Airborne particulate matter (PM) from vehicle exhaust, combustion, road dust and windblown soil, has been associated with increases in respiratory and cardiac morbidity and mortality. PM can occur as coarse particles with a diameter of more than 2.5 μm that generally are derived from natural sources such as soil and sea salts, whereas fine (0.1 to 2.5 μm in diameter) and ultrafine (< .1 μm in diameter) PM occurs as by-products of combustion of fossil fuels. The complexity and seasonal variations of the many components of PM which include metals, nitrates, sulfates, and organic hydrocarbons, make it difficult to identify the precise toxic species that contribute to inflammation, lung disease and cardiovascular effects. However, ultrafine particles, a major component of vehicle emissions that are increased in urban air, may be more pathogenic after inhalation as they have a large surface area per unit mass, a proportionally higher content of toxic hydrocarbons, and increased ability to penetrate into lung tissue. Moreover, inhalation of PM interferes with bacterial inactivation and clearance from the lung.Clinical ramifications of high PM exposures include airway inflammation, exacerbation of asthma, chronic bronchitis and airway obstruction. Large cohort studies also suggest that pollution may increase lung cancer risk . In addiBoth clinical and animal studies implicate oxidative stress and impairment of antioxidant defenses as risk factors in PM-induced cardiovascular responses. Recently, examination of subjects for changes in heart rate variability (HRV) revealed that effects of PM occurred predominantly in people who were missing the glutathione S-transferase M1 (GSTM1) gene, or were obese or hypertensive . Based uAlthough several groups of researchers have shown that cardiac effects can occur in rodents and dogs after acute exposures to concentrated airborne particulates (CAPS), a recent study demonstrates that long-term 6 month) exposure to New York PM at approximately 10× ambient concentrations enhances the formation of atherosclerotic plaques and altered vasomotor tone in susceptible, atherosclerosis-prone mice (Apo E-/- mice) .Although the extremely small size of nanomaterials permits their entry into the circulation and transport potentially to other organs where uptake may also occur, synthetic particles can be engineered in larger size ranges with defined pore dimensions for optimum drug delivery and direct targeting to lung or pleura. Thus nebulization or intrapleural injection circumvents systemic drug toxicity, a central problem in patients with lung cancers and mesotheliomas. Acid-prepared mesoporous spheres (APMS) (1–2 micron diameter with 40 A diameter pores) have been examined in preclinical studies and are nontoxic and noninflammatory after intrapleural injection or intranasal administration into mice . APMS inOccupational exposures to inhaled pathogenic particles and fibers such as silica and asbestos have been associated with the development of lung inflammation and disease. The development of lung fibrosis and cancer by these naturally occurring minerals is dose and time-related with relatively long durations of exposure. In the last decade, epidemiology and animal models have revealed acute morbidity and mortality, including exacerbation of asthma and toxic effects extending to the cardiovascular system, from episodic exposures to PM. Dissecting the adverse components of PM and mechanistic events occurring in the lung, its initial site of deposition, and systemically is daunting because of the complexity and seasonable variability of PM. However, ultrafine particles and components such as metals , sulfates, and adsorbed hydrocarbons may act uniquely or synergistically and/or render the lung more sensitive to secondary insults. The majority of experimental data suggests that size and pro-oxidation state of PM determine its overall distribution and durability in lung and distal organs, cell/tissue transport mechanisms and toxic potential. This information may be vital to the design and use of "safe" synthetic nanoparticles and nanofibers, a burgeoning technology.Proinflammatory and acute effects of PM are directly related to oxidative stress and induction of multiple oxidant or xenobiotic-induced signaling cascades and transcription factors , a paradigm consistent with models of asbestos and silica-associated lung diseases. An important consequence of initial oxidant injury is the antioxidant response that when overwhelmed or compromised in subjects with weakened defenses, i.e., individuals with single nucleotide polymorphisms or changes in expression of antioxidant enzymes, the GSTM1 gene, etc., predisposes to cardiopulmonary morbidity or mortality. Information on other host susceptibility factors and genes predisposing to the development of acute and chronic diseases by inhaled particles may be obtained by genotype and phenotype analyses.Knowledge of the events leading to systemic transport and pathogenicity of PM, including impairment of vascular and fibrinolytic function, is also vital to preventive approaches in the public health domain. The presentations summarized above suggest a number of potential mechanisms whereby PM may adversely affect the cardiovascular system by altering autonomic function, vascular reactivity, and thrombosis. However, how these effects contribute to and whether they are related causally to the pathogenesis of atherosclerosis are unclear. Another important question that needs to be addressed is whether the physical presence of PM is required for distal organ effects or whether these effects are mediated by lung chemokines, cytokines or inflammatory cells after inhalation of PMs. Moreover, the many physical and chemical properties of PM and other inhaled particulates that are central to their pathogenicity need to be elucidated.ACE Angiotensin converting enzymeAM Alveolar macrophagesAP-1 Activator-protein-1APE/Ref-1 Apurinic apyridiminic endonucleaseAPMS Acid-prepared mesoporous spheresApo E-/- mice Atherosclerosis-prone miceARE Antioxidant response elementBALF Bronchoalveolar lavage fluidCAPS Concentrated airborne particulatesCDNP Combustion-derived nanoparticlesCOPD Chronic obstructive pulmonary diseaseCREB cAMP response element binding proteinDEP Diesel exhaust particlesEGFR Epidermal growth factor receptorERK1/2 Extracellular signal regulated kinasesFIP Familial interstitial pneumoniaGSTM1 Glutathione S-transferase M1HB-EGF Heparin-binding epidermal growth factorHRV Heart rate variability8OHdG 8-hydroxydeoxyguanosineIIP Idiopathic interstitial pneumoniaIL-1R Interleukin-1 receptorIPF Idiopathic pulmonary fibrosisJNKs c-Jun-N-terminal kinasesMAPKs Mitogen activated protein kinasesMMP MetalloproteinaseMPO MyeloperoxidaseMt MetallothioneinNF-κB Nuclear factor-κBPI3K Phosphoinositol-3-kinasePM Particulate matterPTPs Protein tyrosine phosphatasesRNS Reactive nitrogen speciesROFA Residual oil fly ashROS Reactive oxygen speciesSSWF Stainless steel welding fumesTNFα Tumor necrosis factor-αVEGF Vascular endothelial growth factorNo authors have competing interests. The findings and conclusions of this report have not been formally disseminated by NIOSH, NIEHS or the EPA and should not be construed to represent any agency determination or policy.All authors participated in the design and coordination of this meeting and helped to draft the manuscript. All authors read and approved the final manuscript.


An increasing number of countries in sub-Saharan Africa are changing to artemisinins combination therapy (ACT) as first or second line treatment for malaria. There is an urgent need to assess the safety of these drugs in pregnant women who may be inadvertently exposed to or actively treated with ACTs.To examine existing published evidence on the relationship between artemisinin compounds and adverse pregnancy outcomes and consider the published evidence with regard to the safety of these compounds when administered during pregnancy.Studies on ACT use in pregnancy were identified via searches of MEDLINE, EMBASE, Cochrane and Current Contents databases. Data on study characteristics, maternal adverse events, pregnancy outcomes and infant follow up were extracted.Fourteen relevant studies  were identified. Numbers of participants in these studies ranged from six to 461. Overall there were reports on 945 women exposed to an artemisinin during pregnancy, 123 in the 1st trimester and 822 in 2nd or 3rd trimesters. The primary end points for these studies were drug efficacy and parasite clearance. Secondary endpoints were birth outcomes including low birth weight, pre-term birth, pregnancy loss, congenital anomalies and developmental milestones. While none of the studies found evidence for an association between the use of artemisinin compounds and increased risk of adverse pregnancy outcomes, none were of sufficient size to detect small differences in event rates that could be of public health importance. Heterogeneity between studies in the artemisinin and comparator drugs used, and in definitions of adverse pregnancy outcomes, limited any pooled analysis.nd and 3rd trimesters and there is not enough evidence to effectively assess the risk-benefit profile of artemisinin compounds for pregnant women particularly for 1st trimester exposure. Methodologically rigorous, larger studies and post-marketing pharmacovigilance are urgently required.The limited data available suggest that artemisinins are effective and unlikely to be cause of foetal loss or abnormalities, when used in late pregnancy. However, none of these studies had adequate power to rule out rare serious adverse events, even in 2 Every year over 50 million pregnancies occur in areas where malaria is endemic, mostly in sub-Saharan Africa. Malaria can have serious consequences for the mother and her baby. In regions where malaria transmission is unstable, pregnant women are at high risk of developing severe malaria, spontaneous abortion, stillbirth or premature delivery. In highThe WHO recommends a three-pronged approach to control of malaria during pregnancy which includes effective case management, intermittent preventive treatment (IPT) and insecticide-treated nets (ITN). Until recently, WHO recommendations for case management during any trimester of pregnancy were chloroquine (CQ), or sulphadoxine-pyrimethamine (SP) in CQ-resistant areas and, alternatively, quinine in areas where neither were effective. There is limited information on the safety profile of most antimalarials used for treatment or prevention of malaria in pregnancy. In a period of increasing parasite resistance to inexpensive, conventional antimalarials such as chloroquine, SP and quinine, there is a pressing need to identify drugs which have the most favourable harm-benefit balance for these vulnerable patients ,4. ArtemElectronic searches were made using MEDLINE/PubMed, EMBASE (1980 – July 2006) databases and through the Cochrane Central Register of Controlled Trials (CENTRAL). Reference lists from identified articles and conference abstracts, including those of the Multilateral Initiative on Malaria (MIM) conference, 2005, and the American Society of Tropical Medicine and Hygiene (ASTMH) annual meeting, 2005, were reviewed. The National Institute of Health's list of clinical trials was searched.Plasmodium falciparum malaria to any artemisinin derivative in, irrespective of whether the participants were symptomatic, have been included in this review. The following data were extracted from reports: setting, year, study design, sample size, characteristics of study participants, drug regimen, and outcomes of interest. Outcomes of interests were: (1) maternal serious adverse events ; (2) maternal non-serious adverse events (3) adverse pregnancy outcomes .Studies on exposure of pregnant women with The internal and external validity of each study was assessed based on reporting comprehensiveness, the representativness of the study population, how bias and confounding factors were accounted for, and the power of the study.Sixty-nine studies of artemisinin-related drugs were identified. However, 55 reports were excluded because they were review papers, animal studies, or because study participants were not pregnant women. Among the fourteen studies that had reported maternal and foetal outcomes of treatment with an artemisinin derivative in pregnancy, five were randomized trials (RCT) and nine were descriptive non-randomized studies. Overall these represent 1,121 women who had been exposed to an artemisinin compound during pregnancy . Taking into account inclusion of women in more than one of the studies reported from the Thai-Burmese border, reports were found of 945 pregnancies exposed to an artemisinin compound (123 in the 1st trimester and 822 in 2nd or 3rd trimesters). The design, characteristics of the study population, type of intervention and outcomes of each study included in the review are shown in Table Five RCTs of artemisinin in pregnant patients have been reported -14. A raet al reported the outcomes of six pregnancies exposed to either artemisinin or artemether. Children of these women were examined 5 to 10 years later for congenital malformation, physical and neurodevelopmental evaluation. No adverse events were reported for the mother or the infants . Other maternal adverse events were described clearly only in the studies conducted at the Thai-Burmese border. In these studies, adverse events that could potentially be associated with the study drug were defined as the occurrence of symptoms after treatment not present at baseline and which occurred before a recrudescence of parasitaemia or a second infection. Data from Thailand and the Thai Burmese border showed that tinnitus and dizziness were significantly less common in the artemisinin treatment group (range 9–64%) compared to the quinine arm (45–79%). Although nausea and vomiting were also significantly less frequent in the artesunate-mefloquine treatment arm in the Thailand study, no significant difference was reported in the Thai-Burmese border trials. Other adverse events were reported with a similar frequency in each treatment group. The most frequent complaints according to these studies were dizziness (range 42–45% for the artemisinin group versus 49–87% for the quinine arm); nausea (range 22–57% and 8–93% respectively); headache (range 21–30% and 30–50% respectively); anorexia (range 7–33% and 0–47% respectively) and muscle and joint pain (range 12–31% and 12–27% respectively). All of these symptoms were also reported on presentation  and so the apparent adverse events may have been due to the underlying malarial episode. Specific neurological evaluation of mothers was performed in four studies,12,17,22Ninety-six percent of the 945 women exposed to an artemisinin in pregnancy were followed up to delivery. Twenty (2.1%) had miscarriages, 19 (2%) stillbirths and 11 (1.2%) neonatal deaths. Six (0.6%) congenital abnormalities were reported ; whereas the expected rate of birth defects in developing countries is about 6% . Of the None of the studies included in this review revealed an increased risk of serious maternal adverse effects, adverse birth outcomes, or neuro-development deficits associated with the use of an artemisinin drug during pregnancy. However, these studies were not designed to assess safety endpoints and, although they were sufficiently powered to answer the original study objective, the studies were under-powered to detect rare safety outcomes, or small differences in adverse event rates, between the comparison groups.The very low prevalence of congenital anomalies reported can partly be explained by the complex nature of birth defect ascertainment; ideally a dysmorphologist should have assessed all newborns for abnormalities that would not be detected by an untrained physician. It was also not possible to assess the expected rate of adverse birth outcomes in any of the study settings due to the lack of background population data on rates for abortions, stillbirths and congenital abnormalities. Four studies which looked for neurological damage following artemisinin exposure revealed no indication of neurotoxicity. However, in the light of recent debates about the potential ototoxicity of the artemisinins, further studies conducting thorough auditory evaluation before and after treatment may be needed -31.The studies reviewed were highly heterogeneous in terms of treatment used, outcomes assessment, population and follow up rate. Different artemisinin drug regimens were used with varying control treatments as a comparator and six studies did not have a control group but compared the rates of adverse birth outcome to community rates derived from separate studies. Most of the studies used an artemisinin derivative combined with another drug, which adds to the difficulty of teasing out individual drug effects and restricts comparison between studies. Four studies used artesunate in combination with mefloquine; use of the latter in pregnancy has caused concern because of an increased risk of stillbirth in women who received this drug during pregnancy in one study  althoughMost of the information on artemisinin exposure during pregnancy comes from studies conducted in Southeast Asia, at the antenatal clinics of the Shoklo Malaria Research Unit among women of the Karen ethnic minority. The RCTs had robust design and randomly allocated treatment groups, although the investigators were not blinded to the treatment group. Follow up of infants varied between these three studies (49 to 80%) and only 46 infants were followed up to one year of age and examined for developmental abnormalities in the non-comparative studies. The women enrolled in these studies are likely to be representative of this population group (Karen ethnic minority) as over 90% of the women in the studied Thai-Burmese border region attend ANCs. These findings cannot be extrapolated directly to sub-Saharan Africa considering geographic differences in parasite species, resistance pattern, transmission intensity and host immunity.nd and 3rd trimester pregnancies. The results of animal studies suggest that if there is a safety issue related to the administration of artemisinins in pregnancy this is likely to occur very early in pregnancy. Only 123 documented first trimester exposures have been reported and this does not provide enough evidence to determine safety. Moreover, an "all or nothing rule" seems to apply for exposure during the first weeks of pregnancy. Animal experiments suggest that congenital abnormalities occur only after exposure over a narrow dose range and over a limited period of time and that exposure usually lead to a normal pregnancy outcome or death of the foetus. Developmental toxicity studies in the monkey confirmed findings from rodent studies; with embryo death induced at therapeutic dose ranges [A number of studies of artemisinin treatment in pregnancy are in progress Table , which we ranges . The tere ranges . An effeUnfortunately, most countries in sub-Saharan Africa do not have the infrastructure and resources for routine pharmacovigilance and very few have a formal system for routine collection of data on possible drug related adverse effects . In induMalaria in pregnancy is a major public health issue and infected pregnant women need prompt treatment with effective drugs. Although artemisinin derivatives and combinations have an excellent efficacy profile, there is very limited data on the safety of artemisinin use during pregnancy particularly in sub-Saharan Africa. Although a few studies of the safety and efficacy of artemisinins during pregnancy are currently underway, these will not produce data on the safety of artemisinins during the first trimester of pregnancy. Post-marketing pharmacovigilance of artemisinin use during pregnancy is needed urgently as ACT is implemented in almost all countries in Africa. Innovative pharmacovigilance tools, methods and systems are needed to monitor the safety of artemisinins and other antimalarials.SD carried out the literature review and wrote the first draft of the paper. SH, DC and BG contributed to the structure and content and were involved in re-drafting the paper.


Cell lines resistant to adriamycin and amsacrine were derived from cloned sublines of the human T cell line Jurkat. Most of the lines resemble atypical MDR cells . Thus, resistant Jurkat sublines were cross resistant to several topoisomerase II inhibiting drugs but had low or no resistance to other classes of drugs, resistance was not reversed by verapamil, Pgp was not overexpressed, and drug accumulation was unaltered in resistant compared to parental (control) sublines. Other findings were that anthracycline metabolism differed between resistant and parental sublines, and that resistant sublines displayed altered expression of small polypeptides (less than 20K MW) and an 85K MW protein. Drug resistant cells showed resistance to the production of drug induced cytogenetic aberrations, DNA breaks, and protein-DNA complexes. Resistance was not mediated by altered binding of drugs to DNA or by increased repair of DNA damage. Indirect evidence suggests that the resistant cells had an altered drug-DNA-topoisomerase II association. The study highlights the complex relationships between DNA breaks, cytogenetic aberrations, protein-DNA complexes and drug cytotoxicity, and shows that the relationships differ for adriamycin and amsacrine, suggesting some differences in the modes of action and/or resistance for the drugs and cell lines.


The prevalence of high resolution profiling of genomes has created a need for the integrative analysis of information generated from multiple methodologies and platforms. Although the majority of data in the public domain are gene expression profiles, and expression analysis software are available, the increase of array CGH studies has enabled integration of high throughput genomic and gene expression datasets. However, tools for direct mining and analysis of array CGH data are limited. Hence, there is a great need for analytical and display software tailored to cross platform integrative analysis of cancer genomes.We have created a user-friendly java application to facilitate sophisticated visualization and analysis such as cross-tumor and cross-platform comparisons. To demonstrate the utility of this software, we assembled array CGH data representing Affymetrix SNP chip, Stanford cDNA arrays and whole genome tiling path array platforms for cross comparison. This cancer genome database contains 267 profiles from commonly used cancer cell lines representing 14 different tissue types.System for Integrative Genomic Microarray Analysis (SIGMA) of cancer genomes, can be accessed at .In this study we have developed an application for the visualization and analysis of data from high resolution array CGH platforms that can be adapted for analysis of multiple types of high throughput genomic datasets. Furthermore, we invite researchers using array CGH technology to deposit both their raw and processed data, as this will be a continually expanding database of cancer genomes. This publicly available resource, the  Array comparative genomic hybridization (CGH) is a method used to detect segmental DNA copy number alterations and is widely used to discover chromosomal aberrations in cancer and other genetic diseases ,2. In thNational Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) repository [European Bioinformatics Institute (EBI) ArrayExpress [With the increasing utilization of array CGH, it has not only become important to establish standards for data deposition, but to develop tools to facilitate public access and to ease mining of available data. Currently, the pository  and EuroyExpress  provide yExpress . HoweverSIGMA) for comparative analysis of multiple genomes.In this study we have created a database consisting of high-resolution, whole-genome array CGH profiles for nearly 200 commonly used cancer cell lines profiled on four different array platforms, which have been instrumental in biochemical and pharmacogenetic studies. Moreover, we have developed a user friendly, web-based java application called the System for Integrative Genomic Microarray Analysis  interrogation of a single sample, (2) visualization and analysis of a single group of samples, (3) comparative analysis of two groups of samples, and (4) integration of data from multiple platforms  locus is amplified only in a subset of samples  with cervical SqCC see . The strSIGMA to allow users to view multiple platforms of data simultaneously. We use the breast cancer cell line, MCF7, to illustrate this functionality. Data from four different array CGH platforms were available publicly: SMRT array, Stanford cDNA microarray, Affymetrix 10K SNP array and the Affymetrix 100K SNP array. Figure Cross platform comparison is essential to the multi-dimensional descriptions of a genome. Here, we have included a feature in et al (2006) compared methylation patterns with copy number profiles in lung cancer cells. Utilizing genomic and epigenetic data from this study for the H1395 lung cancer cell line, we illustrate a parallel display in SIGMA. Figure S100 calcium binding protein A10 (S100A10) gene within this region has been previously shown to be over-expressed in lung cancer [One of the novel features we have provided is the integrative visualization of copy number alterations with DNA methylation status. The major premise in studying copy number alterations at the DNA level is that these are the primary changes involved in driving changes in gene expression. Though gene dosage variation may be responsible for expression changes, alteration in DNA methylation pattern also contributes significantly to regulating gene expression. Recently, methods for global methylation analysis to measure aberrant DNA methylation status across tumor genomes have been developed -12. Wilsg cancer . It is rSIGMA application facilitates consolidation and structuring of diverse sources of array CGH data into a repository that is accessible with a new easy-to-use built-in web-based analytical application. The launch version contains data for 267 array CGH profiles, representing cancer cell lines of over 14 different types of tissue. The ability of SIGMA to incorporate multiple array CGH platforms facilitates the archiving of array CGH data from future publications, regardless of current or future array platform used. Though currently SIGMA's architecture facilitates the direct mining of genomic and epigenomic data, this can be easily adapted, and not limited to, high resolution genetic and gene expression surveys.We have developed an application for the integrative cross platform analysis of array CGH data. The NCBI GEO [Stanford Microarray Database [The raw data for 267 CGH profiles in the database was obtained from a variety of sources. They include both published and unpublished data ,15-22. PNCBI GEO , StanforDatabase  or websiDatabase , the earDatabase ,20, the Database ,13. For Java WebStart application interface allowing users to formulate queries and perform visualization, an Apache Web Service which facilitates the connection of the user application to the database and a relational database which is implemented using MySQL  identification (if applicable), array platform used and the description of the cancer type as part of the schema. For two channel array-based profiles, the dye which was used to label the sample is also recorded. Lastly, mapping information pertaining to a clone or probe and its position in the genome is kept in file with a fixed format, such that subsequent improvements and updates to the genomic positioning of the array elements can be easily incorporated. Moreover, since individual microarray software platforms use their own map version, map information for all platforms were compiled based on data from the UCSC Genome Browser [ Browser . CurrentdChip [et al. (2004) were referenced against 12 normal individuals and the NCI-60 profiles were referenced against 6 normal diploid controls. The gender of the profiles were not specified, hence data from the X chromosome may not be an accurate reflection. Segmentation of all data was performed using aCGH-Smooth [Data for each platform were processed as similarly as possible. SMRT array data were normalized using the stepwise framework for normalization with default parameters . SimilardChip  with defH-Smooth , with daSIGMA: System for Integrative Genomic Microarray AnalysisCGH: Comparative Genomic HybridizationSNP: Single Nucleotide PolymorphismProject name: SIGMA Project home page: Operating system(s): Platform independentProgramming language: JavaOther requirements: Java version 1.6+License: Free for academic and research use, commercial users please request special permissionRC designed and developed SIGMA and wrote the manuscript. WWL and BPC were involved in the design and development. AC, DM and AT were the programmers. JJD was involved with initial design and CM provided manuscript editing and program feedback. WLL is the principal investigator of the lab.List of cell lines in database. Detailed description of all the cell lines.Click here for fileSingle group visualization. Whole genome frequency plot of lung adenocarcinoma.Click here for fileTwo group whole genome comparison. Whole genome frequency plot comparison of squamous cancer of the lung and cervix.Click here for file


In this article we describe the methodologic approaches of the Pew Environmental Health Commission at the Johns Hopkins Bloomberg School of Public Health used to identify priority environmental health conditions and develop recommendations to establish a national environmental public health tracking network. We present the results of a survey of public health and environmental practitioners to uncover state and local health tracking needs and priorities. We describe the steps that combined the findings from the state and local health tracking survey and a review of the state of the science on environmental impacts on health to identify priority health end points. Through an examination of national health and health care databases, we then describe trends and public health effects of those diseases that may be linked to the environment. Based on this analysis, respiratory diseases and neurologic diseases are recommended as priorities for tracking. Specific end points recommended for tracking include asthma and chronic respiratory diseases, and chronic neurodegenerative diseases such as multiple sclerosis. Based on trends in reported prevalence, consideration should also be given to developmental disabilities, reproductive disorders, and endocrine/metabolic disorders. Strengthening of current efforts to track cancer and birth defects should also be included as components of a nationwide health tracking network. Finally, we present the recommendations for environmental public health tracking. These recommendations provided the groundwork for the development of the Centers for Disease Control and Prevention’s National Environmental Public Health Tracking Progam that now includes 21 states, three cities, and three academic centers throughout the nation. The new millennium has brought unprecedented challenges and opportunities for the advancement of public health. Scientific breakthroughs provide new insights into the genetic basis of health and disease, while analytical advances allow the identification and measurement of previously unrecognized threats. The translation of this new knowledge to effective prevention will require new approaches to evaluating the interaction of health and environment. Despite the many advances in identification, measurement, and control of contaminants in the environment, fundamental questions about the role of environmental exposures in human disease remain unanswered. This information gap includes a number of chronic diseases and conditions that may be increasing in prevalence, including asthma, neurologic disorders, developmental disabilities, and even diabetes.a) identify populations at risk and respond to outbreaks, clusters and emerging threats; b) establish the relationship between environmental hazards and disease; c) guide intervention and prevention strategies, including lifestyle improvements; d) identify, reduce, and prevent harmful environmental risks; e) improve the public health basis for policymaking; f ) enable the public’s right to know about health and the environment; and g) track progress toward achieving a healthier nation and environment.The Pew Environmental Health Commission at the Johns Hopkins Bloomberg School of Public Health was established in 1998 to develop a blueprint to rebuild the nation’s public health defenses against environmental threats, including the ability to track hazards, environmental exposures, and health outcomes. Greater capacity in tracking can help investigators In 1999–2000 the Pew Environmental Health Commission’s Tracking Project  conducteWe describe a multistep approach to address the goals of the Pew Commission’s tracking project. First, we describe the development and implementation of a tracking survey administered to public health and environmental practitioners. Second, we describe steps taken to inform the selection of priority health end points for environmental health tracking, which included a synthesis of review articles on environmental health indicators and an examination of existing national environmental emissions, health, and health care databases to understand trends in environmentally related health end points. Finally, we discuss the process for translating the findings from our research to Pew Commission recommendations.n = 49) were primarily environmental epidemiologists. Local respondents (n = 21 counties) were mostly health department directors who had expressed interest in environmental public health, suggesting a best-case scenario. Representatives included all 12 local representatives on the National Association of City and County Health Officials (NACCHO) Environmental Health and Prevention Advisory Committee in addition to 10 local health departments randomly selected from a NACCHO list of 133 local health departments that identified environmental health as an interest area. Surveys were conducted from March to September 2000. A follow-up survey is under way in 2004.State and local public health practitioners were surveyed by telephone to obtain information about their environmental public health tracking programs. Questions focused on organization, data collection and use, financial and technical resources, barriers, and priorities. State respondents . These listings were derived from toxicologic and epidemiologic studies and information from regulatory agencies. The U.S. Environmental Protection Agency (EPA) Toxics Release Inventory  served as the starting point for the chemical listings. The Scorecard ranking exercises combined the TRI data with information on potential health hazards of these substances. These reports account only for pollution from industrial facilities that reported to TRI in 1997  and include only the 644 chemicals covered by TRI at that time.We used the Environmental Defense Scorecard analysis that provides listings of chemicals that impact human health . However, four National Center for Health Statistics (NCHS) national survey data sets including the National Health Interview Survey (NHIS), the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), and the National Hospital Discharge Survey (NHDS) were examined for this analysis and provided useful insights into some of the end points identified in steps 1 and 2 ; 2004d.International Classification of Diseases, 9th Revision (ICD-9) codes and that have been linked to identifiable exposures to environmental agents  and personal air monitoring data  States reported the following for health outcome tracking activities. Most states tracked cancer (94%), infectious outbreaks (80%), and birth defects (69%), but many did not track asthma (55%) and few tracked emerging environmental health concerns such as developmental disabilities (16%), learning disorders (12%), or autoimmune diseases (8%). Some of the larger local public health agencies collected significant quantities of tracking data, but many locals relied on other agencies to collect data, often seeing their role more in dissemination and follow-up investigations.To improve their effectiveness and leverage limited capacities, state and local officials worked with other federal, state, and local agencies on environmental public health issues. Often, state public health departments facilitated relationships between federal and local agencies. Given the coordination challenges, 53% of states and 81% of local departments designated lead individuals for overseeing tracking activities.Among states, major sources of funding for environmental public health tracking were state general funds (81% of states), federal funds from grants and cooperative agreements with the Centers for Disease Control and Prevention (CDC), the Agency for Toxic Substances and Disease Registry (ATSDR), the U.S. EPA and the National Institute for Occupational Safety and Health , prevention block grants (32%), and fee-based regulatory programs (21%). At the local level, 90% of departments received local general funds, and 86% received funds from fees and permits to support their tracking activities. Forty-eight and 38% of departments, respectively, received state department of health and environment funding, and only 33% received federal funding. From a technologic perspective, 81% of the states indicated that health and environmental data were electronically available for internal use, and 69% made health data available to the public in limited electronic formats and geographic scales. Local public health departments varied widely in their access to current computer software and/or hardware, and in their ability to use technology to its full extent. The lack of standardization in state, county, and other data systems hindered the ability to access and interpret data.States revealed a diverse set of priorities for environmental public health tracking. Drinking water, metals, food protection, asthma, cancer, and for some states, the need to establish basic tracking capacity and assure room for flexible approaches to tracking were top priorities. At the local level, top priorities, as reflected by spending, were food protection, waste management, and water and air quality. Further priority needs included indoor air, bioterrorism and emergency response, and land use issues.At both the state and local levels, the greatest identified barrier to effective environmental public health tracking was scarce financial resources, followed by the related need for staff. Respondents wanted flexible funding strategies and increases in staff and expertise. Local agencies were particularly concerned about unfunded tracking recommendations or requirements. Other important barriers included a lack of political will, limited reporting requirements, lack of established databases, and their own organizational structure. Further, some wanted guidance on tracking system design, implementation, and priorities.Through the literature review, we identified key health outcomes partially determined by environmental exposures. In 1993 the ATSDR authored a report  that ideIn 1994 Turning to the international literature, Regarding the connections between air pollution and mortality, particularly respiratory and cardiovascular mortality, The U.S. Department of Health and Human Services (U.S. DHHS) Healthy People initiative regularly tracks the public’s health and has set objectives for quantifiable reductions in disease and disability over the past 20 years. Community health and environmental health indicators drawn from Healthy People objectives included asthma and chronic obstructive pulmonary disease, chronic liver disease and cirrhosis, heart disease, methemoglobinemia, congenital anomalies, low birth weight, developmental disabilities, kidney diseases, cancer and endocrine disorders including diabetes mellitus .Based on the reviews of the Scorecard data and related health categories, we found that substances with potential respiratory effects were the highest category of releases in 1997 and this continues to be the highest ranking category based on 2001 TRI data. Neurologic, skin, gastrointestinal, and liver toxicants were next highest categories in total pounds released. Based on 2001 data, these categories have shifted slightly, with skin disorders replacing neurologic conditions in the second highest category and gastrointestinal diseases moving up to the third category. Other categories included cardiovascular, developmental, and reproductive effects.We also evaluated trend data over the same time period within specific health categories. For example, within respiratory conditions, asthma rates increased by 38.6% and chronic bronchitis increased by 15.3%. For endocrine and metabolic diseases, thyroid disorders increased by 36.3% and diabetes mellitus increased by 19.1% over this time period. For neurologic diseases, multiple sclerosis increased by 21.2% and migraine headaches increased by 26%. Within the reproductive health category, prostate diseases  increased by 48% and disorders of female reproductive organs  increased by 28.6%.We also summarized the number of hospital discharges, emergency department visits, hospital outpatient care visits, and doctor office visits for six broad groupings of health outcomes, including lung and respiratory conditions, neurologic conditions, reproductive and fertility conditions, blood disorders, liver disease, and cardiovascular disorders. Specific disease end points within these broad classifications were included where information was available.Cardiovascular diseases required the most health care resources, including over 48 million doctor visits and 4.6 million hospitalizations. Although pollution exposures have been indicated for some types of cardiovascular diseases, many other environmental risk factors, including lifestyle and obesity, have been implicated as contributing causes. Lung and respiratory diseases (33.6 million doctor visits and over 3 million emergency department visits) and neurologic conditions (8.7 million doctor visits) also required large amounts of health care services. Of all the lung and respiratory health conditions resulting in utilization of the health care system, asthma and chronic bronchitis accounted for the largest proportion of hospital, emergency department, outpatient and doctor visits in 1996. Among the endocrine conditions, diabetes resulted in the most health care use (over 15 million physician visits). Of the neurologic conditions requiring health care, a relatively small fraction was due to neurodegenerative diseases such as senility, cerebral degeneration, and Alzheimer and Parkinson diseases. However, these diseases have a devastating impact on the quality of life and require care that may not be measured by these surveys.Summit participants developed specific recommendations for improving the national environmental health infrastructure and capacity for tracking. They did not identify specific exposures or health end points for tracking. Recognizing current scientific limitations concerning the role of environment in disease and state and regional differences in environmental health priorities, they recommended a flexible tiered approach. Recommendations includedNational tracking of high priority exposures and health outcomesA sentinel network to identify emerging hazardsA coordinated network of pilot regional, state, and local tracking programsA supportive research program to guide and evaluate tracking progressThese recommendations provided the basis for the Pew Commission recommendations that have shaped the development of the CDC Environmental Public Health Tracking Program.The surveys of state and local public health department officials provided baseline data on the state of environmental public health tracking in 2000. The surveys found great variety in tracking organization, functions, and resources among state and local health departments. The overall infrastructure for environmental public health tracking lacked adequate support, personnel, coordination, and data resources. Collection of these baseline data will provide an opportunity to evaluate the impact of the new tracking initiatives and resources as well as increased focus on preparedness since 2000.The priority health condition analysis identified a number of limitations that must be addressed. These findings are constrained by available epidemiologic and toxicologic data and are driven by high-volume chemical release reporting under the TRI. Multiple health effects can be associated with an individual toxicant, and complex interactions between toxicants can further affect human health. Nevertheless, this approach provided the Pew Commission with a starting point for identifying the categories of health end points to be considered for tracking. Given the large amount of toxic pollutants released, there is a need to improve the tracking of population exposures and look for any evidence of adverse health impacts.The end points identified through the literature represent conditions for which environmental exposures have been implicated or are pre-existing health conditions that may be exacerbated by exposure to environmental pollutants. The end points also reflect agency priorities, including ATSDR’s seven broad categories of priority health conditions and the U.S. DHHS Healthy People objectives for community and environmental health indicators . AlthougAn examination of available national survey data indicated that the reported prevalence of several categories of disease potentially related to the environment has been increasing. Between 1986 and 1995 the largest increases were reported in endocrine and metabolic disorders (21.7%), followed by neurologic (20%) and respiratory diseases (20%). Reproductive disorders also increased during this time (7.3%).Available data on health care utilization for these outcomes indicate that cardiovascular disease requires the greatest use of health care, with respiratory (over 33 million doctor visits and 3 million emergency department visits) and neurologic diseases (over 8 million doctor visits) also requiring large amounts of health care services.Based on this analysis of the weight of evidence and trends in health outcomes and impacts, respiratory diseases and neurologic diseases are recommended as priorities for tracking. Specific end points recommended for tracking include asthma and chronic respiratory diseases, and chronic neurodegenerative diseases such as multiple sclerosis. Based on increasing trends in reported prevalence and the potential for environmental exposures to increase population risks, consideration should also be given to developmental disabilities, reproductive disorders, and endocrine and metabolic disorders. Strengthening of current efforts to track cancer and birth defects should also be included as components of a nationwide environmental health tracking network.The role of the environment in the etiology of these health outcomes remains unknown. Identification of specific outcomes as tracking priorities should not be interpreted as an implication of environmental causality. However, the increasing incidence and prevalence of a number of diseases with potential links to environmental exposures underscores the need for improved tracking to increase our understanding of risk factors, identify populations at high risk, inform priorities for research, and develop coordinated prevention efforts.Advances in hazard identification, exposure assessment, health outcome data collection, and information technology provide mechanisms for advancing tracking and improving our understanding of the environment and health. These advances, coupled with deep public concern, provide a window of opportunity to strengthen the national infrastructure for environmental health information, expand public access to this important information, and protect the privacy of individuals. New technologies in biomonitoring have the potential to transform the nation's capacity to track exposures to pollutants and understand their impacts on health. Advances in communication and information technology have expanded opportunities for public access and given us new tools to analyze, map, and disseminate health data. New technology also can improve safeguards to protect the confidentiality of identifiable personal health information.a) build environmental public health capacity, b) increase collaboration between environment and health agencies, c) identify and evaluate environmental and health data systems, d) build partnerships with nongovernmental organizations and communities, and e) develop model systems that link environmental and health data and that other states or localities can use. Three public health schools are funded to support state and local health departments and investigate possible links between health effects and the environment  have developed a set of environmental public health indicators that can be used to assess baseline status and trends and build core surveillance capacity in state and local agencies . The U.SBeyond these indicator programs, the CDC’s biomonitoring program and “National Report on Human Exposure to Environmental Chemicals” are enhancing our abilities to measure environmental chemicals in the human body . The datBeyond strengthening the science and supporting data, efforts are under way to better link environment and health, including new relationships and collaboration between environment and health agencies. This integrated thinking brings new understandings and approaches to improve environmental protection efforts, to better characterize and control sources through public health surveillance, and to understand the links between adverse exposures and health effects.The “building blocks” of knowledge provided by a nationwide environmental public health tracking network will enable scientists to answer many of the troubling questions we are asking today about what is making us sick. The result will be new prevention strategies aimed at reducing and ultimately preventing many of the chronic diseases and disabling conditions that afflict millions of Americans.