Toward hyperuniform disordered plasmonic nanostructures for reproducible surface-enhanced Raman spectroscopy.

We report on the self-assembling of clusters of gold-nanoparticles (Au-NPs) directed by the phase separation of poly(styrene)-b-poly(methylmethacrylate) (PS-b-PMMA) block-copolymer (BCP) on indium tin oxide coated glass, which induces the onset of vertical lamellar domains. After thermal evaporation of gold on BCP, Au-NPs of 4 nm are selectively included into PS-nanodomains by thermal annealing, and then clustered with large density of hot spots (> 10(4) µm(2)) in a random two-dimensional pattern. The resulting nanostructure exhibits near-hyperuniform long-range correlations. The consequent large degree of homogeneity of this isotropic plasmonic pattern gives rise to a highly reproducible Surface-Enhanced Raman Scattering (SERS) enhancement factor over the centimeter scale (std. dev. ∼ 10% over 0.25 cm(2)). We also discuss the application of a static electric field for modulating the BCP host morphology. The electric field induces an alignment of Au-NP clusters into ordered linear chains, exhibiting a stronger SERS activity, but reduced SERS spatial reproducibility.

Rest perfusion abnormalities in hypertrophic cardiomyopathy: correlation with myocardial fibrosis and risk factors for sudden cardiac death.

AIM: To measure the prevalence of abnormal rest perfusion in a population of consecutive patients with known hypertrophic cardiomyopathy (HCM) referred for cardiovascular MRI (CMR), and to assess any associations between abnormal rest perfusion and the presence, pattern, and severity of myocardial scar and the presence of risk factors for sudden death. MATERIALS AND METHODS: Eighty consecutive patients with known HCM referred for CMR underwent functional imaging, rest first-pass perfusion, and late gadolinium enhancement (LGE). RESULTS: Thirty percent of the patients had abnormal rest perfusion, all of them corresponding to areas of mid-myocardial LGE and to a higher degree of segmental hypertrophy. Rest perfusion abnormalities correlated with more extensive and confluent LGE. The subgroup of patients with myocardial fibrosis and rest perfusion abnormalities (fibrosis+/perfusion+) had more than twice the incidence of episodes of non-sustained ventricular tachycardia on Holter monitoring in comparison to patients with myocardial fibrosis and normal rest perfusion (fibrosis+/perfusion-) and patients with no fibrosis and normal rest perfusion (fibrosis-/perfusion-). CONCLUSIONS: First-pass perfusion CMR identifies abnormal rest perfusion in a significant proportion of patients with HCM. These abnormalities are associated with the presence and distribution of myocardial scar and the degree of hypertrophy. Rest perfusion abnormalities identify patients with increased incidence of episodes of non-sustained ventricular tachycardia on Holter monitoring, independently from the presence of myocardial fibrosis.

Patient characteristics and symptoms associated with perceived coercion during hospital treatment.

OBJECTIVE: Large numbers of psychiatric patients either are involuntarily admitted to hospital treatment or feel coerced despite a legally voluntary admission. For ethical and clinical reasons, their perceived coercion should be reduced as far as possible. There is however limited evidence on patient characteristics associated with perceived coercion during hospital treatment. This study aimed to identify i) sociodemographic and clinical characteristics associated with perceived coercion at admission and ii) changes in symptoms and global functioning associated with changes in perceived coercion over time. METHOD: Three thousand and ninety three in-patients who were involuntarily admitted or felt coerced to hospital treatment despite a legally voluntary admission were recruited in the European evaluation of coercion in psychiatry and harmonization of best clinical practice - EUNOMIA project in 11 European countries. Perceived coercion, global functioning and symptoms were assessed after admission and at a 3-month follow-up. RESULTS: Involuntary admission, female gender, poorer global functioning and more positive symptoms were associated with higher levels of perceived coercion at admission. Perceived coercion significantly decreased over time, and the improvements in global functioning and positive symptoms were associated with reduction in perceived coercion. CONCLUSION: Female patients perceive more coercion in psychiatric hospital treatment. Effective treatment for positive symptoms and improving patients' global functioning may lead to a reduction in perceived coercion.

Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptor α and ß.

Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen-dependent and -independent prostate cell (PC) lines via activation of ERß and an antagonistic effect on ERα. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen-dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERß and lacked ERα. In EPN cells, there was an increase in the pre-G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl-2 mRNA and Bcl-2 protein levels were significantly reduced, while activated caspase-3 and Par-4 levels increased significantly after either E2 or RAL treatment; in addition, c-myc transcript was inhibited after 10(-6) M RAL treatment. A dose-dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase-3 activation and Par-4 increase after either E2 or RAL treatment; while c-myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell-specific, depending on ERß or ERß/ERα relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non-genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression.

Microdomain patterns from directional eutectic solidification and epitaxy

Creating a regular surface pattern on the nanometre scale is important for many technological applications, such as the periodic arrays constructed by optical microlithography that are used as separation media in electrophoresis, and island structures used for high-density magnetic recording devices. Block copolymer patterns can also be used for lithography on length scales below 30 nanometres (refs 3-5). But for such polymers to prove useful for thin-film technologies, chemically patterned surfaces need to be made substantially defect-free over large areas, and with tailored domain orientation and periodicity. So far, control over domain orientation has been achieved by several routes, using electric fields, temperature gradients, patterned substrates and neutral confining surfaces. Here we describe an extremely fast process that leads the formation of two-dimensional periodic thin films having large area and uniform thickness, and which possess vertically aligned cylindrical domains each containing precisely one crystalline lamella. The process involves rapid solidification of a semicrystalline block copolymer from a crystallizable solvent between glass substrates using directional solidification and epitaxy. The film is both chemically and structurally periodic, thereby providing new opportunities for more selective and versatile nanopatterned surfaces.

[The IPSEMA initiative on health and safety at the maritime work place]. / Iniziative dell'IPSEMA in materia di salute e sicurezza nei luoghi di lavoro marittimo.

IPSEMA, founded in 1994 on former Casse Marittime institute, provides insurance to maritime workers from work injuries and occupational disease. According to current law IPSEMA, together with INAIL and ISPESL is engaged in the field of workplace safety and health, and in its promotion. For this purpose, IPSEMA is involved in injuries and diseases monitoring and in technical education. Recently ISPEMA has published "Quaderni di Formazione per la Sicurezza a Bordo delle Navi" and the research results on physical agent-based dams realized together with INSEAN. IPSEMA is now involved, with INMP institute, in "Salute in Mare" project in order to realize an information campaign on sea workers' self-health and health education.

Long-term physical training allows high exercise performance in moderate chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is a major health problem, because of its prevalence, morbidity and mortality. As a result of symptoms such as cough and dyspnea patients with COPD suffer from exercise limitation and reduced health related quality of life. The present paper reports the case of a 67-year old ex-smoker patient with COPD, who had exercised regularly since when he was young, and maintained a better exercise capacity than healthy people of the same age, despite a forced expiratory volume in 1 second of the 60% of the predicted normal value. This case suggests that regular physical exercise in COPD patients may prevent the loss of exercise capacity despite significant airway obstruction.

Prediction of the health effects of polychlorinated biphenyls (PCBs) and their metabolites using quantitative structure-activity relationship (QSAR).

Polychlorinated biphenyls (PCBs) are a group of 209 persistent environmental contaminants that are slightly different but structurally related. PCBs are known to induce a variety of health effects and often have been toxicologically tested as complex commercial mixtures (Aroclors) but environmental exposure occurs separately to a small number of specific congeners. Recently, the Third National Report on Human Exposures to Environmental Chemicals, an assessment of exposure data of the National Health and Nutrition Examination Survey (NHANES), identified 35 individual PCB congeners in the U.S. population. These types of findings necessitate the toxicity evaluation of individual congeners but adequate toxicity data for most individual PCB congeners are not available. Due to this, a quantitative structure-activity relationship (QSAR) approach was used to assess the potential mutagenesis and carcinogenesis of individual congeners and their possible metabolites. The predictions were analyzed to define the underlying generalizations between the parent PCBs, their metabolites, and some important toxicological endpoints. This analysis reveals that (1) mono and di-chlorinated PCBs and their metabolites can be potential mutagens; (2) PCB benzoquinone metabolites could be carcinogenic but the weight of evidence is poor. These results support the hypothesis that environmental exposure to some PCBs and/or their metabolites could produce mutagenicity and/or carcinogenicity. Hence, these data should be considered as priority toxicological testing data needs. As with all computational toxicology analytical findings, these conclusions must yield to empirical data as they become available.

Combination of all-trans-retinoic acid and gemtuzumab ozogamicin in an elderly patient with acute promyelocytic leukemia and severe cardiac failure.

All-trans-retinoic acid (ATRA) combined with anthracyclines is currently the standard treatment for acute promyelocytic leukemia (APL). In elderly patients the presence of comorbidities, such as cardiomyopathy or different organ failures, often represents an absolute contraindication to standard chemotherapy. In this particular setting of patients, alternative front-line approaches are needed. Here we report the use of gemtuzumab ozogamicin as consolidation therapy in a 68-year-old patient not eligible for standard dose anthracycline due to severe cardiac failure and chronic anticoagulant therapy, affected by low-risk APL. Induction therapy was started with ATRA alone, at a dose of 45 mg/m2 for 80 days. The patient obtained a complete hematological and molecular remission. At day +170 the patient was treated with 6 mg/m2 gemtuzumab ozogamicin monthly for two months (2 total doses) as a consolidation therapy and then started a maintenance program with ATRA 45 mg/m2 for 15 days every three months, for a total time of two years. No adverse events were observed in every phase of treatment and the patient is still in complete continuous hematological and molecular remission 29 months from diagnosis. This approach represents an intriguing therapeutic option to be investigated in randomized studies in low- and intermediate-risk elderly patients (older than 65 years), aiming to minimize or to eliminate standard chemotherapy in advantage of new non-conventional agents, including ATO.

[Surgical treatment of sinus pilonidalis by Dufourmentel's flap technique]. / Il trattamento chirurgico del sinus pilonidalis con trasposizione di lembo secondo Dufourmentel.

The present study reports the results of surgical treatment of 175 consecutive chronic pilonidalis sinus cases by excision alone, excision and primary closure, excision and Dufourmentel's flap technique. The analysis of hospital stay , average recovery time, patient compliance and percentages of failures and recurrences enables us to state that Dufourmentel's technique is the best choice, allowing fast recovery with minimal discomfort and lower rate of recurrence. Moreover the good compliance of the technique and the use of recently introduced more effective local anaesthetics have allowed us to plan the treatment in a day-surgery setting with good clinical results.

Cellular events accompanying regression of skin recurrences of breast carcinomas treated with intralesional injections of natural interferons alpha and gamma.

Cutaneous recurrences of breast carcinomas were treated with 10 i.l. injections of nIFNs alpha and gamma delivered in combination (7 lesions) or singly (11 with nIFN-alpha, one with nIFN-gamma). Histologically confirmed complete regressions occurred in 5 of 7 lesions treated with nIFN-alpha/nIFN-gamma and in 5 of 11 recurrences injected with nIFN-alpha alone. In all cases specimens were obtained before and after therapy. In addition, in some cases (4 treated with nIFN-alpha/nIFN-gamma, 2 with nIFN-alpha, one with nIFN-gamma) multiple recurrences were injected simultaneously and were excised 24 h after 1, 3, and 10 injections and 21 days after completion of therapy. The main findings observed in the treated lesions undergoing complete and partial regressions included: (a) inhibition of mitotic activity and up-regulation of antigenic expression (mammary epithelial membrane antigen, intercellular adhesion molecule 1, HLA-DR) by the carcinoma cells; (b) activation of macrophages and dendrocytes with marked expression of HLA-DR and HLA-A,B,C; (c) infiltration of the dermis and tumors by activated T-lymphocytes (CD3+, CD4+, CD8+); (d) questionable participation by B-lymphocytes and natural killer cells; (e) activation of endothelium with enhancement of antigenic expression (intercellular adhesion molecule 1, HLA-DR), procoagulant activity, and vascular permeability. The responses elicited by nIFN-alpha/nIFN-gamma were greater than those caused by either IFN used alone. It appears that in these patients the IFNs exerted an antiproliferative action and potentiated a cell-mediated immunological response liminally present in the neoplastic tissues prior to therapy.

Detection of estrophilin in frozen sections of breast cancers using an estrogen receptor immunocytochemical assay.

Estrogen receptor (ER) was detected in frozen sections of 36 breast carcinomas using an antiestrophilin monoclonal antibody according to an immunocytochemical technique elaborated and made available by Abbott Laboratories in the form of a kit (ER-immunocytochemical assay monoclonal). Immunostaining was confined to the nuclei of the carcinoma cells. In all positive specimens, nuclei with different staining intensities were present in addition to a variable number of unstained nuclei, presumably because of functional heterogeneity. Of the 36 carcinomas, 27 displayed positive immunostaining, 4 had no staining, and in 5 the staining was borderline. All specimens were assayed for ER content by the dextran-coated charcoal (DCC) technique. When the DCC values were compared with the results of immunostaining it was found that 4 tumors were negative and 27 were positive by both techniques, whereas of 5 cases with borderline staining 3 were negative by DCC and 2 had low DCC values. These correlations proved to be highly significant (P much less than 0.001). The number of stained nuclei (extent of staining) related to the DCC status in a significant manner (P less than 0.01), whereas the intensity of staining did not (P greater than 0.10). These results indicate that immunocytochemical visualization of ER using Abbott's "ER-Immunocytochemical Assay Monoclonal" kit is an easy, reproducible, and reliable technique.

Feasibility of a psychoeducational family intervention for people with bipolar I disorder and their relatives: Results from an Italian real-world multicentre study.

BACKGROUND: Despite several guidelines recommend the use of psychoeducational family interventions (PFIs) as add-on in the treatment of patients with bipolar I disorder, their implementation on a large scale remains limited. The aim of the present study is to identify obstacles for the feasibility of PFIs in routine care. METHODS: This was a multicentre, real-world, controlled, outpatient trial, carried out in 11 randomly recruited Italian mental health centres. Two mental health professionals from each center attended a modular training course on PFI and provided the intervention. Difficulties and benefits experienced by mental health professionals in implementing the intervention were assessed through the Family Intervention Schedule (FIS-R), which was administered six times. RESULTS: Sixteen out of the 22 recruited professionals completed the training and administered the PFI to 70 patients with bipolar I disorder and their relatives. The retention rate of families receiving the intervention was 93%. Mental health professionals reported high levels of organizational difficulties, several benefits in their daily clinical work and low levels of intervention-related difficulties. The most important organizational obstacles were related to the need to integrate the intervention with other work responsibilities and to the lack of time to carry out the intervention. These difficulties did not decrease over time. Intervention-related difficulties were rated as less problematic since the first time assessment and tended to improve over time. LIMITATIONS: Low number of recruited professionals; use of a not previously validated assessment instrument. CONCLUSIONS: PFIs are feasible in routine care for the treatment of patients with bipolar I disorder and their relatives, and main obstacles are related to the organization/structure of mental health centres, and not to the characteristics of the intervention itself.

Perceived insecurity, mental health and urbanization: Results from a multicentric study.

AIMS: This article aims to (1) explore the levels of perceived insecurity in a sample of patients with mood or anxiety disorders and (2) assess whether living in 'big cities' can influence the levels of patients' perceived insecurity and social contacts compared to living in a non-urbanized context. METHODS: A total of 24 Italian mental health centers (MHCs) have been invited to participate. Twenty patients consecutively accessing the MHC have been recruited. All patients have been assessed using validated assessment tools. RESULTS: The sample consisted of 426 patients, mostly female, with a mean age of 45 years. Globally, 52.2% of patients had a diagnosis of mood disorders, and 37.8% had anxiety disorders. Half of the sample declared that the main feeling toward life is uncertainty; higher levels of pessimistic views toward life have been detected in patients living in urban areas. A positive association between negative attitudes toward life and higher levels of depressive and anxiety symptoms, poor social functioning and higher levels of perceived psychological distress has been found. CONCLUSION: Our findings confirm the presence of a common sense of perceived uncertainty among our sample. Such attitude toward life can have a detrimental impact on patients' psychological and physical well-being, contributing to high levels of distress.

Regression of human breast cancer xenografts in response to intralesional treatment with interferons alpha and gamma potentiated by tumor necrosis factor.

The potentiating effects of human recombinant tumor necrosis factor-alpha (rTNF-alpha) on the antitumor actions of recombinant interferon-gamma (rIFN-gamma) and of natural interferons alpha and gamma combined (nIFN-alpha/nIFN-gamma) were studied on human breast cancer xenografts growing bilaterally in nude mice. The cytokines were injected singly or in combination in one of the two tumors of each mouse to study local effects while the opposite tumor was left undisturbed to evaluate systemic effects. The tumors received 20 intralesional injections (four cycles of 5 daily injections each). In injected tumors the best results were obtained with nIFN-alpha/nIFN-gamma supplemented with rTNF-alpha. The responses were dose dependent, resulting in complete regression of 9 of 9 tumors with rTNF-alpha used at the dose of 5 micrograms per injection, of 6 of 8 tumors at the dose of 2.5 micrograms, and of 4 of 8 tumors at the dose of 0.5 microgram. Mostly mild to moderate partial responses were seen in the other groups. The systemic effects on the contralateral tumors were significantly less than the local effects on the corresponding tumors. Histologically, responding tumors showed reactive fibrosis and inflammatory cell infiltration. No vascular alterations were seen, presumably because of the immunodeficiency of nude mice. It was concluded that the potentiation of the antitumor actions of IFNs by rTNF-alpha was effective at the local but not at the systemic level.

Immunostaining of estrogen receptor in paraffin sections of breast carcinomas using monoclonal antibody D75P3 gamma: effects of fixation.

Immunostaining of estrogen receptor was carried out on paraffin sections of breast carcinomas using an anti-estrophilin monoclonal antibody (D75P3 gamma) and the avidin-biotin technique. The tumors were fixed in Bouin's solution or in formalin for varying periods of time at room temperature or at 4 degrees C. Best results were obtained following fixation in Bouin's at room temperature or in formalin at 4 degrees C. The staining was localized in the nuclei of carcinoma cells and was heterogeneous in intensity and extent. Prolonged fixation resulted in decreased immunoreactivity and in the appearance of nonspecific cytoplasmic and background staining. The estrogen receptor immunostaining on paraffin sections was found to be in concordance with that on frozen sections (Abbott ER-ICA) and with the steroid-binding assay (dextran-coated charcoal) in over 90% of the cases. This method is of easy and rapid execution and yields reliable and reproducible results.

Gene induction studies and toxicity of chemical mixtures.

As part of its mixtures program, the Agency for Toxic Substances and Disease Registry (ATSDR) supports in vitro and limited in vivo toxicity testing to further our understanding of the toxicity and health effects of chemical mixtures. There are increasing concerns that environmental chemicals adversely affect the health of humans and wildlife. These concerns have been augmented by the realization that exposure to chemicals often occurs to mixtures of these chemicals that may exhibit complex synergistic or antagonistic interactions. To address such concerns, we have conducted two studies with techniques that are being used increasingly in experimental toxicology. In the first study, six organochlorine pesticides (4,4 -DDT, 4,4 -DDD, 4,4 -DDE, aldrin, dieldrin, or endrin) were selected from the ATSDR Comprehensive Environmental Response, Compensation and Liability Act of 1980 (or Superfund) priority list and tested for their ability to modulate transcriptional activation of an estrogen-responsive reporter gene in transfected HeLa cells. In these assays, HeLa cells cotransfected with an expression vector encoding estrogen receptor and an estrogen-responsive chloramphenicol acetyltransferase (CAT) reporter plasmid were dosed with and without selected environmental chemicals either individually or in defined combinations. Estradiol consistently elicited 10- to 23-fold dose-dependent inductions in this assay. By contrast, all six of the organochlorine pesticides showed no detectable dose-related response when tested either individually or in binary combinations. Thus, these chemicals as binary mixtures do not exhibit any additional estrogenicity at the levels tested in these assays. In the second study, arsenic [As(V)], cadmium [Cd(II)], chromium [Cr(III, VI)], and lead [Pb(II)] were tested in a commercially developed assay system, CAT-Tox (L), to identify metal-responsive promoters and to determine whether the pattern of gene expression changed with a mixture of these metals. This assay employs a battery of recombinant HepG2 cell lines to test the transcriptional activation capacity of xenobiotics in any of 13 different signal-transduction pathways. Singly, As(V), Cd(II), Cr(III, VI), and Pb(II) produced complex induction profiles in these assays. However, no evidence of synergistic activity was detected with a mixture of Cd(II), Cr(III), and Pb(II). These results have shown metal activation of gene expression through several previously unreported signal-transduction pathways and thus suggest new directions for future studies into their biochemical mechanisms of toxicity. In conclusion, the (italic)in vitro(/italic) methods used in these studies provide insights into complex interactions that occur in cellular systems and could be used to identify biomarkers of exposure to other environmental chemical mixtures.

Public health challenges posed by chemical mixtures.

Approximately 40 million people live within a 4-mile radius of waste sites that the Agency for Toxic Substances and Disease Registry (ATSDR) has assessed to date. Human populations living in the vicinity of such sites are often subjected to complex chemical exposures that may contribute to the total body burden of oxogenous chemicals. Apart from the contaminants found at waste sites, exposure may also include environmental, occupational, and personal agents. Concurrent exposure to chemicals such as welding fumes, indoor air pollutants, tobacco smoke, alcohol, and prescription and nonprescription drugs makes the health assessment of exposure to waste site chemicals a more complex task. Voluntary exposures such as these frequently entail exposures to relatively high chemical concentrations and can usually be well defined and quantified. Conversely, involuntary exposures from waste sites may be at low concentrations and hence difficult to characterize and quantify. Of the approximately 1450 waste sites evaluated by the ATSDR, 530 (37%) had either completed or potentially completed exposure pathways. Results of public health assessments conducted at 167 sites during 1993 to 1995 show that about 1.5 million people have been exposed to site-specific contaminants. At 10% or more of the sites that had either completed or potentially completed exposure pathways, 56 substances were identified. Of these, 19 are either known or anticipated human carcinogens, and 9 are associated with reproductive or endocrine-disrupting effects. In this paper we present important concerns regarding hazardous waste sites including the impact on human health, ecology, and quality of life. To address such human-health related issues, the ATSDR has established a mixtures program that consists of three components: trend analysis to identify combinations of chemicals of concern, experimental studies to identify data that would be useful in the development and implementation of predictive decision support methodologies, and development of assessment methodologies and guidance to provide health assessors with the tools to incorporate the evaluation of multiple-chemical exposure into site assessments.

Public health implications of environmental exposures.

The Agency for Toxic Substances and Disease Registry (ATSDR) is a public health agency with responsibility for assessing the public health implications associated with uncontrolled releases of hazardous substances into the environment. The biological effects of low-level exposures are a primary concern in these assessments. One of the tools used by the agency for this purpose is the risk assessment paradigm originally outlined and described by the National Academy of Science in 1983. Because of its design and inherent concepts, risk assessment has been variously employed by a number of environmental and public health agencies and programs as a means to organize information, as a decision support tool, and as a working hypothesis for biologically based inference and extrapolation. Risk assessment has also been the subject of significant critical review. The ATSDR recognizes the utility of both the qualitative and quantitative conclusions provided by traditional risk assessment, but the agency uses such estimates only in the broader context of professional judgment, internal and external peer review, and extensive public review and comment. This multifaceted approach is consistent with the Council on Environmental Quality's description and use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment in concert with risk assessment to define plausible exposure ranges of concern rather than a single numerical estimate that may convey an artificial sense of precision. In this approach biomedical opinion, host factors, mechanistic interpretation, molecular epidemiology, and actual exposure conditions are all critically important in evaluating the significance of environmental exposure to hazardous substances. As such, the ATSDR risk analysis approach is a multidimensional endeavor encompassing not only the components of risk assessment but also the principles of biomedical judgment, risk management, and risk communication. Within this framework of risk analysis, the ATSDR may rely on one or more of a number of interrelated principles and approaches to screen, organize information, set priorities, make decisions, and define future research needs and directions.