Tissue distribution and histopathological effects of titanium dioxide nanoparticles after intravenous or subcutaneous injection in mice.

Nanoparticles can be formed following degradation of medical devices such as orthopedic implants. To evaluate the safety of titanium alloy orthopedic materials, data are needed on the long-term distribution and tissue effects of injected titanium nanoparticles in experimental animals. In this study, we evaluated the tissue distribution and histopathological effects of titanium dioxide (TiO(2)) nanoparticles (approximately 120 nm diameter) in mice after intravenous (i.v.; 56 or 560 mg kg(-1) per mouse) or subcutaneous (s.c.; 560 or 5600 mg kg(-1) per mouse) injection on two consecutive days. Animals were examined 1 and 3 days, and 2, 4, 12 and 26 weeks after the final injection. When examined by light microscopy, particle agglomerates identified as TiO(2) were observed mainly in the major filtration organs - liver, lung and spleen - following i.v. injection. Particles were still observed 26 weeks after injection, indicating that tissue clearance is limited. In addition, redistribution within the histological micro-compartments of organs, especially in the spleen, was noted. Following s.c. injection, the largest particle agglomerates were found mainly in the draining inguinal lymph node, and to a lesser extent, the liver, spleen and lung. With the exception of a foreign body response at the site of s.c. injection and the appearance of an increased number of macrophages in the lung and liver, there was no histopathological evidence of tissue damage observed in any tissue at any time point.

Age-related differences in susceptibility to cisplatin-induced renal toxicity.

Limited experimental models exist to assess drug toxicity in pediatric populations. We recently reported how a multi-age rat model could be used for pre-clinical studies of comparative drug toxicity in pediatric populations. The objective of this study was to expand the utility of this animal model, which previously demonstrated an age-dependent sensitivity to the classic nephrotoxic compound, gentamicin, to another nephrotoxicant, namely cisplatin (Cis). Sprague-Dawley rats (10, 25, 40 and 80 days old) were injected with a single dose of Cis (0, 1, 3 or 6 mg kg(-1) i.p.). Urine samples were collected prior and up to 72 h after treatment in animals that were >or= 25 days old. Several serum, urinary and 'omic' injury biomarkers as well as renal histopathology lesions were evaluated. Statistically significant changes were noted with different injury biomarkers in different age groups. The order of age-related Cis-induced nephrotoxicity was different than our previous study with gentamicin: 80 > 40 > 10 > 25 day-old vs 10 >or= 80 > 40 > 25-day-old rats, respectively. The increased levels of kidney injury molecule-1 (Kim-1: urinary protein/tissue mRNA) provided evidence of early Cis-induced nephrotoxicity in the most sensitive age group (80 days old). Levels of Kim-1 tissue mRNA and urinary protein were significantly correlated to each other and to the severity of renal histopathology lesions. These data indicate that the multi-age rat model can be used to demonstrate different age-related sensitivities to renal injury using mechanistically distinct nephrotoxicants, which is reflected in measurements of a variety of metabolite, gene transcript and protein biomarkers.

Social disadvantage, mental illness and predictors of legal involvement.

The following study evaluates the complex association between legal involvement and mental illness. It describes a population of consumers of community mental health programs, comparing those with legal involvement to those without legal involvement, on a number of demographic, clinical and social indicators. It is a secondary analysis of data collected in studies making up the Community Mental Health Evaluation Initiative (CMHEI) in the province of Ontario, Canada. Legal involvement was a significant issue among community mental health program consumers; about one in five consumers had at least some contact with the legal system in the preceding nine months. Legally involved consumers were more likely to be in receipt of social assistance and be unstably housed than those legally uninvolved. However, there were no significant differences between legally involved and uninvolved consumers with respect to severity of symptomatology, current medication use or number of hospitalization days in the past 9 months. A predictive model compared the differential impact of clinical and social determinants upon legal involvement. Analyses failed to uncover a significant relationship between severity of psychiatric symptomatology and legal involvement. Significant predictors of legal involvement included gender, race, drug use as well as housing instability, and receipt of social assistance. Legal involvement was attributable to factors other than the severity of mental illness; these results challenge assumptions that the most symptomatically severe consumers are most at risk of legal involvement. Accordingly, the rate of legal involvement in a sample of community mental health program users must be considered in a broad context, with particular emphasis on social disadvantage.

Effects of beta-estradiol and bisphenol A on heat shock protein levels and localization in the mouse uterus are antagonized by the antiestrogen ICI 182,780.

Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestrogens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An examination of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to an understanding of its mechanism of action. In this study we examined the dose-related effects of BPA on levels of a suite of heat shock proteins (hsps) and on the localization of hsp90alpha, a chaperone of the ER, in uteri of ovariectomized B6C3F1 mice and compared these effects with those of beta-estradiol (E2). The antiestrogen ICI 182,780 (ICI) was co-administered with BPA or E2 in order to examine the potential role of the ER. BPA, although less potent than E2, increased hsp90alpha and grp94 to similar levels, but was much less effective than E2 in increasing levels of hsp72. Treatment with 100 mg BPA/kg/day or 2 microg E2/kg/day increased hsp90alpha to 300% of control levels and altered its tissue expression pattern. In uteri of corn oil (control)-treated mice, hsp90alpha predominantly localized in the cytoplasm and nuclei of epithelial cells. Upon treatment with BPA or E2 there was increased intensity of staining in the stroma and myometrium, and in the epithelium hsp90alpha was localized almost exclusively in the cytoplasm. The effects of BPA or E2 on hsp levels and hsp90alpha localization were attenuated by ICI. These results suggest an involvement of the ER in BPA- and E2-induced increases in uterine levels of hsp90alpha, grp94, and hsp72, and localization of hsp90alpha.

Lessons learned from trends in psychotropic drug expenditures in a canadian province.

Although prescription drug prices are lower in Canada than in the United States, trends indicate that there has nevertheless been a steep increase in expenditures on psychotropic drugs. Between 1992 and 1998, such expenditures increased by 216 percent; 61 percent of these expenditures were on antidepressants, 33 percent on antipsychotics, and less than 7 percent on anxiolytics. Most of the increase in costs in Canada is attributable to a greater use of newer agents and the higher prices of these agents. These trends are a reminder not only that the use of newer, more expensive psychotherapeutic agents has become a widely embraced part of care but also that lower drug prices do not necessarily insulate a health care system from rising expenditures. The authors' findings prompt the questions of whether the use of these newer agents meets practice guidelines and whether there are ways to control the increases in drug expenditures while ensuring high-quality care.

Using financial incentives to promote shared mental health care.

OBJECTIVES: To consider the most common primary care reimbursement structures, to identify incentives inherent in each, and to discuss how each could be used to encourage a shared-care approach to treating mental disorders at the primary care level. METHOD: Three major financial reimbursement models--fee-for-service, capitation, and blended payment mechanisms--are examined. Each is considered in terms of its risk-sharing elements and the consequent incentives. We offer several scenarios to illustrate how the shared-care practice model might be encouraged under each financing mechanism. RESULTS: The current fee-for-service system does not encourage shared care. For wide adoption of the shared-care practice model, there must be a change in the reimbursement system's incentives. While none of the financing mechanisms offers a perfect solution, each has potential. Each, however, must be carefully tailored to its environment. CONCLUSIONS: Financial considerations are just one aspect to achieving shared care. Nevertheless, in designing a system to encourage collaborative, coordinated care for those suffering from mental illness, decision makers should be wary of creating or maintaining obstacles (financial or otherwise) to provision of accessible, high-quality care.

Needs-based planning: evaluation of a level-of-care planning model.

With the closure of a number of provincial psychiatric hospitals planned, the Ministry of Health of Ontario has commissioned a series of planning projects to identify alternative placements for current hospital patients. The goal is to match need to care in the least restrictive setting. A systematic, clinically driven planning process was implemented that involved three steps: development of a continuum of levels of care representing increasingly intensive and more restrictive supports, development of criteria and decision rules for placement, and comprehensive needs assessment of current patients using the Colorado Client Assessment Record. Results showed that only 10% of current inpatients need to remain in the hospital, and over 60% could live independently in the community with appropriate supports. Evidence supports concurrent validity of the planning model, but further work is needed to assess whether recommended levels of care effectively meet consumer needs in the least restrictive setting.

Comparisons of men with full or partial eating disorders, men without eating disorders, and women with eating disorders in the community.

OBJECTIVE: The authors compared 62 men who met all or most of the DSM-III-R criteria for eating disorders with 212 women who had similar eating disorders and 3,769 men who had no eating disorders on a wide variety of clinical and historical variables. METHOD: The groups of subjects were derived from a community epidemiologic survey performed in the province of Ontario that used the World Health Organization's Composite International Diagnostic Interview. RESULTS: Men with eating disorders were very similar to women with eating disorders on most variables. Men with eating disorders showed higher rates of psychiatric comorbidity and more psychosocial morbidity than men without eating disorders. CONCLUSIONS: These results confirm the clinical similarities between men with eating disorders and women with eating disorders. They also reveal that both groups suffer similar psychosocial morbidity. Men with eating disorders show a wide range of differences from men without eating disorders; the extent to which these differences are effects of the illness or possible risk factors for the occurrence of these illnesses in men is not clear.

Using forecasting models to estimate the effects of changes in the composition of claims for selective serotonin reuptake inhibitors on expenditures.

BACKGROUND: The use of selective serotonin reuptake inhibitors (SSRIs) as antidepressant therapy has increased considerably since the introduction of fluoxetine in 1989. By 1999, 3 of the 4 available SSRIs were among the top 10 most frequently used drugs in the United States. In addition, SSRIs were one of the major contributors to the growth in psychotropic medication expenditures during the past 5 years. OBJECTIVE: The purpose of this article was to examine the utilization patterns of the 4 most commonly used SSRIs and their contribution to rising antidepressant medication expenditures among claimants in a publicly funded drug program. Using the results of forecasting models, we explored possible ways to control these growing expenditures. METHODS: Cross-sectional antidepressant claims and expenditure data from the Ontario Drug Benefits program for 1992 to 1998 were examined. Five scenarios were modeled in which future SSRI expenditures and claims were predicted using exponential smoothing models. RESULTS: If the historical patterns of use continued, a 20% increase in the 1998 level of expenditures was expected to occur by the year 2000. Predicted expenditures are sensitive to the composition of the SSRI claims. Exclusive use of 1 of the 4 major SSRIs (fluvoxamine, fluoxetine, paroxetine, and sertraline) could decrease projected expenditures by 30% or increase them by 11%. An "equal shares" approach, in which each of the 4 SSRIs are used in equal proportions in the population, may reduce expenditures by approximately 8%. CONCLUSIONS: The current trends in the utilization data suggest that sertraline and paroxetine are being used as first-line treatments. The results of the forecasting models suggest that growing expenditures could be curbed if these 2 antidepressants were not used in that manner. Short of limiting the drugs available on benefit formularies, there may be a way to control costs through the use of a prescribing algorithm. Although our results support the use of fluoxetine for first-line SSRI treatment as a cost-control measure, we do not definitively recommend its adoption. These findings contribute to the discussion about using fixed versus flexible formularies as a potential cost-control mechanism.

Educating the public about mental illness and homelessness: a cautionary note.

OBJECTIVE: To determine whether the viewing of a video depicting the successful struggles of homeless persons with mental illness in finding and maintaining housing can have a positive impact on attitudes toward homeless persons with mental illness. METHOD: Five hundred and seventy-five high school students attending a brief educational session on mental illness participated in 1 of 3 comparison versions of the 2-hour program (control, video, video plus discussion). All completed an "Attitudes toward Homelessness and Mental Illness Questionnaire." Demographic and prior exposure variables were entered as a covariates in between-group analyses of variance. RESULTS: Females and subjects who had more prior encounters with homeless persons were found to have the most positive attitudes. After controlling for these effects, the video alone had a negative impact on attitudes relative to the other groups, while the video followed by a discussion with one of the people featured in it had a largely positive impact. CONCLUSIONS: The apparent immediacy and the evocative power of video presentations cannot substitute for direct contact for the purpose of promoting positive attitude change. The findings are consistent with prior research emphasizing the importance of direct interaction with members of stigmatized groups to reduce negative attitudes. Education programs trying to destigmatize mental illness and homelessness using videos should proceed with caution.

Effects of particulate and soluble cadmium species on biochemical and functional parameters in cultured murine macrophages.

Cultured murine macrophages (RAW 264.7) were used to evaluate the temporal relationships between cytotoxicity, phagocytosis, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production, and alterations in expression of stress proteins after exposure to cadmium oxide (CdO) or cadmium chloride (CdCl(2)), particulate and soluble forms of cadmium, respectively. Macrophages were exposed in vitro to CdO (25 or 50 microg) or CdCl(2) (30 or 40 microM) for 2 to 72 h. Cytotoxicity was not evident until 18 h when exposed to 30 microM CdCl(2) or 25 microg CdO, but occurred as early as 12 h after exposure to 40 microM CdCl(2) or 50 microg CdO. Relative to untreated controls, phagocytic activity decreased progressively from 2 to 24 h after exposure to both forms of cadmium. TNF-alpha levels increased to 2- to 3-fold after 4 h and remained elevated until 24 h after exposure to 25 and 50 microg CdO and 30 microM CdCl(2), but decreased by 18-24 h at 40 microM CdCl(2). CdCl(2) or CdO alone did not induce NO; however, both cadmium species reduced lipopolysaccharide (LPS)-stimulated NO production in a dose-dependent manner. Enhanced de novo synthesis of 70- and 90-kD heat shock, or stress, proteins was observed 2 to 8 h after exposure to both CdCl(2) and CdO; however, synthesis of these proteins returned to control levels by 24 h. Stress protein synthesis was enhanced by CdCl(2) or CdO prior to cytotoxicity, but coincided with a decrease in phagocytic capacity and an increase in TNF-a levels. The data suggest that cultured macrophages respond similarly in vitro to a particulate form and a soluble form of cadmium in a cell type that plays a pivotal role in inflammatory and immune responses.

Personality assessment of homeless adults as a tool for service planning.

The psychiatric status of homeless adults has been described primarily in terms of Axis I disorders. By adding a subset of the Personality Assessment Inventory, this study tests the feasibility and usefulness of a brief, self-administered questionnaire to obtain scores on several dimensions of personality. Cluster analysis sorted 112 tested subjects into four groups characterized by distinct profiles. Two of these were characterized by extreme scores on pathological dimensions of personality (borderline features, antisocial traits, and aggressivity) and differed primarily on the dimension of suicidality. The third reflected moderate levels of personality dysfunction and the fourth did not deviate from adult nonclinical norms. The validity of the clusters was supported by demographic, background, and diagnostic subgroup differences. Brief personality assessment can be a cost-effective approach to matching services with clinical needs of homeless adults by attending to interpersonal dimensions that will likely affect service provision.

Bisphenol A-induced increase in uterine weight and alterations in uterine morphology in ovariectomized B6C3F1 mice: role of the estrogen receptor.

The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in the rodent remains controversial, and few studies have previously examined the effects of BPA on uterine morphology. Furthermore, it is not known whether BPA-induced uterotrophic effects are, similarly to beta-estradiol (E(2)), mediated through the estrogen receptor (ER). In this study, we compared the effects of BPA on uterine wet weight and morphology to those of E(2) in the B6C3F1 ovariectomized mouse. To examine whether these effects were mediated through the ER, the antiestrogen ICI 182, 780 (ICI) was co-administered with BPA or E(2). We report that subcutaneous administration of BPA at doses between 0.8 and 8 mg/day over 4 days significantly increased mean uterine wet weights above those of vehicle (corn oil)-treated mice. The uterine weight data suggest that BPA acts as a partial agonist with an EC(50) of 0.72 mg/day compared to 19.4 ng/day for E(2). BPA (2 mg/day) and E(2) (40 ng/day) induced a significant increase in luminal epithelial height and in the thickness of both the stromal and myometrial layers of the uterus. The effects of 40 ng E(2)/day on all endpoints studied were reversed by 20 microg ICI/day. ICI at 200, but not 20 microg/day, was able to reverse the BPA (2 mg/day)-induced increase in both uterine wet weight and luminal epithelial height. ICI alone at 200 microg/day stimulated an increase in thickness of both the stroma and myometrium and did not reverse the effects of BPA (2 mg/day) on these layers. These results suggest that the BPA-induced increase in uterine wet weight and in luminal epithelial height in the ovariectomized B6C3F1 mouse are mediated by the ER.

Tertiary mental health services: I. Key concepts.

There are some individuals with severe and persistent mental illnesses who cannot be managed by primary and secondary services and who require tertiary care. Such clients are characterized by aggressiveness, noncompliance with medication, and dangerousness. Tertiary care program elements include psychosocial rehabilitation, sophisticated medication management, and behavioural approaches. Tertiary care may be delivered through assertive community treatment and/or specialized outreach teams, community residential programs, or hospital-based services. Increasingly, organized systems have been developed to ensure that individuals meet criteria for tertiary care and receive the most appropriate level of care. Most importantly, the delivery of tertiary care must not be tied to particular settings or time frames, and level of care must be delinked from model or location of care in order to create flexible, efficient, effective mental health services.

Tertiary mental health services: II. Subpopulations and best practices for service delivery.

Tertiary care subpopulations are characterized by having more than one significant condition, each of which has been traditionally dealt with by different systems of care. They experience severe and persistent mental illness and one or more of the following: age-related physical or medical conditions, substance use disorders, developmental handicaps, and acquired brain injury. This paper provides estimates of prevalence for each of these subgroups and discusses best practices which have developed in response to their special needs.

Narratives of identity: re-presentation of self in people who are homeless.

The problem of homelessness is a pressing social and health concern ascribed to the interaction between personal, social, economic, and service system resources. The article is based on a qualitative study of the experiences of 29 homeless individuals. In-depth interviews were conducted with single adult shelter users. Analysis revealed the self to be a process that was continually developing. Participants tacitly locate their self-concepts in the past, present, and future. These time frames reflect the form and content of self. They also reveal hopes, dreams, beliefs, and understandings about self. The ways in which homelessness discredits notions of self and personal identity, and the hierarchy of identify with which homeless individuals use to cope are also examined.

Mercury induces regional and cell-specific stress protein expression in rat kidney.

Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat-shock proteins (hsps) and glucose-regulated proteins (grps) are members of a large superfamily of proteins collectively referred to as stress proteins. This particular stress-protein response has evolved as a cellular strategy to protect, repair, and chaperone other essential cellular proteins. The objective of this study was to evaluate the differential expression of four hsps in the renal cortex and medulla during experimental nephrotoxic injury using HgCl2. Male Sprague-Dawley rats received single injections of HgCl2 (0.25, 0.5, or 1 mg Hg/kg, i.v.). At 4, 8, 16, or 24 h after exposure, kidneys were removed and processed for histopathologic, immunoblot, and immunohistochemical analyses. Nephrosis was characterized as minimal or mild (cytoplasmic condensation, tubular epithelial degeneration, single cell necrosis) at the lower exposures, and progressed to moderate or severe (nuclear pyknosis, necrotic foci, sloughing of the epithelial casts into tubular lumens) at the highest exposures. Western blots of renal proteins were probed with monoclonal antibodies specific for 4 hsps. In whole kidney, Hg(II) induced a time- and dose-related accumulation of hsp72 and grp94. Accumulation of hsp72 was predominantly localized in the cortex and not medulla, while grp94 accumulated primarily in the medulla but not cortex. The high, constitutive expression of hsp73 did not change as a result of Hg(II) exposure, and it was equally localized in cortex and medulla. Hsp90 was not detected in kidneys of control or Hg-treated rats. Since hsp72 has been shown involved in cellular repair and recovery, and since Hg(II) damage occurs primarily in cortex, we investigated the cell-specific expression of this hsp. Hsp72 accumulated primarily in undamaged distal convoluted tubule epithelia, with less accumulation in undamaged proximal convoluted-tubule epithelia. These results demonstrate that expression of specific stress proteins in rat kidney exhibits regional heterogeneity in response to Hg(II) exposure, and a positive correlation exists between accumulation of some stress proteins and acute renal cell injury. While the role of accumulation of hsps and other stress proteins in vivo prior to or concurrent with nephrotoxicity remains to be completely understood, these stress proteins may be part of a cellular defense response to nephrotoxicants. Conversely, renal tubular epithelial cells that do not or are unable to express stress proteins, such as hsp72, may be more susceptible to nephrotoxicity.

Becoming and remaining homeless: a qualitative investigation.

This article reports the qualitative findings of a multimethod study of the homeless population in Toronto, Canada. The qualitative component sought to identify how people become homeless and why some individuals remain homeless for an extended period of time or cycle in and out of homelessness (the chronically homeless). In-depth, semistructured interviews were conducted with 29 homeless adults. The findings suggest that people both become and remain homeless due to a combination of macro level factors (poverty, lack of employment, low welfare wages, lack of affordable housing) and personal vulnerability (childhood abuse or neglect, mental health symptoms, impoverished support networks, substance abuse). Chronically homeless individuals often reported experiences of severe childhood trauma and tended to attribute their continued homelessness to a substance abuse problem. It is concluded that both macro and individual level factors must be considered in planning programs and services to address the issue of homelessness in Canada.