Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model.

The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition (n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls (P < 0.05). These data show that different enrichment strategies affect behaviour and disease progression in a transgenic mouse model, and may have implications for the effects of these strategies on experimental outcomes.

Increased versican content is associated with tendinosis pathology in the patellar tendon of athletes with jumper's knee.

Expansion of the extracellular matrix is a prominent but poorly characterized feature of tendinosis. The present study aimed to characterize the extent and distribution of the large aggregating proteoglycan versican in patients with patellar tendinosis. We obtained tendon from tendinopathy patients undergoing debridement of the patellar tendon and from controls undergoing intramedullary tibial nailing. Versican content was investigated by Western blotting and immunohistochemistry. Microvessel thickness and density were determined using computer-assisted image analysis. Markers for smooth muscle actin, endothelial cells (CD31) and proliferating cells (Ki67) were examined immunohistochemically. Western blot analysis and immunohistochemical staining revealed elevated versican content in the proximal patellar tendon of tendinosis patients (P=0.042). Versican content was enriched in regions of fibrocartilage metaplasia and fibroblast proliferation, as well as in the perivascular matrix of proliferating microvessels and within the media and intima of arterioles. Microvessel density was higher in tendinosis tissue compared with control tissue. Versican deposition is a prominent feature of patellar tendinosis. Because this molecule is not only a component of normal fibrocartilagenous matrices but also implicated in a variety of soft tissue pathologies, future studies should further detail both pathological and adaptive roles of versican in tendons.

Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

OBJECTIVES: To establish the relative effectiveness and cost of providing a home-based exercise programme versus home-based exercise supplemented with an 8-week class-based exercise programme. DESIGN: The trial was a pragmatic, single-blind randomised clinical trial accompanied by a full economic evaluation. SETTING: Patients were randomly allocated to either home-based exercise or home exercise supplemented with class exercise programmes. PARTICIPANTS: A total of 214 patients, meeting the American College of Rheumatology's classification of knee osteoarthritis, were selected from referrals from the primary and secondary care settings. INTERVENTIONS: Both groups were given a home exercise programme aimed at increasing lower limb strength, and endurance, and improving balance. The supplemented group also attended 8 weeks of twice-weekly knee classes run by a physiotherapist. Classes represented typical knee class provision in the UK. MAIN OUTCOME MEASURES: Assessments of locomotor function, using a timed score of three locomotor activities, walking pain and self-reported disability with the Western Ontario and McMaster's Universities osteoarthritis index (WOMAC) were made. General health, lower limb strength, range of movement and compliance with exercise were also measured. Patients were assessed before and after treatment, and also at 6- and 12-month follow-ups. The economic evaluation looked at health service resource use and assessed cost-effectiveness by relating differential costs to differences in quality-adjusted life-years (QALYs) based on patients' responses to the EuroQol-5 Dimensions. Data were obtained at baseline, 1 month, 6 months and 12 months through face-to-face interviews and, where appropriate, examination of hospital medical records. RESULTS: Patients from the supplemented group demonstrated significantly greater improvement in locomotor function and decrease in pain while walking at all follow-ups. The supplemented group also demonstrated smaller but significant improvements in balance, strength, WOMAC score, and the physical function and pain dimensions of the Short Form-36. However, not all of these improvements were maintained over the 12-month follow-up period. There was no evidence that compliance with the home exercise programme was different or that total costs or mean QALY gains were significantly different between the groups. However, costs were slightly lower and QALY gains slightly higher in the group with the supplementary class-based programme. The economic evaluation suggests that supplemented programmes are likely to be considered cost-effective, although there is uncertainty around this estimate, with approximately 30--35% probability that the intervention would not be cost-effective. CONCLUSIONS: The supplementation of a home-based exercise programme with a class-based exercise programme led to superior improvement in the supplemented group. These differential improvements were still evident at review 12 months after treatment had ceased. The additional cost of the supplemented group was offset by reductions in resource use elsewhere in the system. Compliance with the home exercise programme did not differ between the groups. Based on this evidence, the supplementation of a home-based exercise programme with an 8-week class-based exercise programme can be confidently expected to produce small improvements in locomotor function and clinically important reductions in pain. It is recommended that future research investigates methods of increasing compliance with home exercise programmes and evaluates the impact of these interventions in the primary care setting, where most patients with knee osteoarthritis are managed.

What do we mean by the term "inflammation"? A contemporary basic science update for sports medicine.

Most practicing sports medicine clinicians refer to the concept of "inflammation" many times a day when diagnosing and treating acute and overuse injuries. What is meant by this term? Is it a "good" or a "bad" process? The major advances in the understanding of inflammation in recent years are summarised, and some clinical implications of the contemporary model of inflammation are highlighted.

Palmitoylation of the Rous sarcoma virus transmembrane glycoprotein is required for protein stability and virus infectivity.

The Rous sarcoma virus (RSV) transmembrane (TM) glycoprotein is modified by the addition of palmitic acid. To identify whether conserved cysteines within the hydrophobic anchor region are the site(s) of palmitoylation, and to determine the role of acylation in glycoprotein function, cysteines at residues 164 and 167 of the TM protein were mutated to glycine (C164G, C167G, and C164G/C167G). In CV-1 cells, palmitate was added to env gene products containing single mutations but was absent in the double-mutant Env. Although mutant Pr95 Env precursors were synthesized with wild-type kinetics, the phenotypes of the mutants differed markedly. Env-C164G had properties similar to those of the wild type, while Env-C167G was degraded faster, and Env containing the double mutant C164G/C167G was very rapidly degraded. Degradation occurred after transient plasma membrane expression. The decrease in steady-state surface expression and increased rate of internalization into endosomes and lysosomes paralleled the decrease in palmitoylation observed for the mutants. The phenotypes of mutant viruses were assessed in avian cells in the context of the pATV8R proviral genome. Virus containing the C164G mutation replicated with wild-type kinetics but exhibited reduced peak reverse transcriptase levels. In contrast, viruses containing either the C167G or the C164G/C167G mutation were poorly infectious or noninfectious, respectively. These phenotypes correlated with different degrees of glycoprotein incorporation into virions. Infectious revertants of the double mutant demonstrated the importance of cysteine-167 for efficient plasma membrane expression and Env incorporation. The observation that both cysteines within the membrane-spanning domain are accessible for acylation has implications for the topology of this region, and a model is proposed.

Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway.

The role of membrane-type (MT) 2-matrix metalloproteinase (MMP) in the cellular activation of MMP-2 and the tissue inhibitor of matrix metalloproteinase (TIMP) requirements for this process have not been clearly established. To address these issues a TIMP-2-free cell line derived from a Timp2-/- mouse was transfected for stable cell surface expression of hMT2-MMP. Untransfected cells did not activate endogenous or exogenous TIMP-2-free MMP-2 unless both TIMP-2 and concanavalin A (ConA) were added. Transfected cells expressing hMT2-MMP efficiently activated both endogenous and exogenous MMP-2 (within 4 h) via the 68-kDa intermediate in the absence of TIMP-2 and ConA. In contrast, activation of MMP-2 by Timp2-/- cells expressing recombinant hMT1-MMP occurred more slowly (12 h) and required the addition of 0.3-27 nm TIMP-2. Addition of TIMP-2 or TIMP-4 did not enhance MMP-2 activation by MT2-MMP at any concentration tested; furthermore, activation was inhibited by both TIMPs at concentrations >9 nm, consistent with the similar association rate constants (k(on)) calculated for the binding of TIMP-4 and TIMP-2 to MT2-MMP (3.56 x 10(5) m(-1) s(-1) and 6.52 x 10(5) m(-1) s(-1), respectively). MT2-MMP-mediated activation involved cell surface association of the MMP-2 in a hemopexin carboxyl-terminal domain (C domain)-dependent manner: Exogenous MMP-2 hemopexin C domain blocked activation, and cells expressing hMT2-MMP did not bind or activate a truncated form of MMP-2 lacking the hemopexin C domain. These studies demonstrate the existence of an alternative TIMP-2-independent pathway for MMP-2 activation involving MT2-MMP, which may be important in mediating MMP-2 activation in specific tissues or pathologies where MT2-MMP is expressed.

Fatalism and risk of adolescent depression.

This research examined fatalism, the belief in external control over life chances, as a risk factor for adolescent depression. Data were analyzed from a large (N = 5,423) sample of adolescents attending middle school in an ethnically diverse community in the southwest. It was hypothesized that adolescents who demonstrated greater fatalism would have a higher risk for depression. Bivariate associations between fatalism and depression were substantial, with an odds ratio (OR) of nearly 25 for depression with impairment and nearly 13 for depression without impairment. Adjustment for the effects of 10 covariates drawn from three domains (status attributes, stressors, and personal/social resources) essentially eliminated the association between fatalism and depression with impairment. However, the OR was still 2.6. The significant association between fatalism and depression without impairment (OR = 2.7) remained after adjustment for covariates. The results provide further support for models of depression which emphasize the role of psychosocial deficits. In this case, we found depression was associated not only with greater fatalism but also greater pessimism, lower self-esteem, more passive coping, and less social support.

Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation.

On the cell surface, the 59-kDa membrane type 1-matrix metalloproteinase (MT1-MMP) activates the 72-kDa progelatinase A (MMP-2) after binding the tissue inhibitor of metalloproteinases (TIMP)-2. A 44-kDa remnant of MT1-MMP, with an N terminus at Gly(285), is also present on the cell after autolytic shedding of the catalytic domain from the hemopexin carboxyl (C) domain, but its role in gelatinase A activation is unknown. We investigated intermolecular interactions in the gelatinase A activation complex using recombinant proteins, domains, and peptides, yeast two-hybrid analysis, solid- and solution-phase assays, cell culture, and immunocytochemistry. A strong interaction between the TIMP-2 C domain (Glu(153)-Pro(221)) and the gelatinase A hemopexin C domain (Gly(446)-Cys(660)) was demonstrated by the yeast two-hybrid system. Epitope masking studies showed that the anionic TIMP-2 C tail lost immunoreactivity after binding, indicating that the tail was buried in the complex. Using recombinant MT1-MMP hemopexin C domain (Gly(285)-Cys(508)), no direct role for the 44-kDa form of MT1-MMP in cell surface activation of progelatinase A was found. Exogenous hemopexin C domain of gelatinase A, but not that of MT1-MMP, blocked the cleavage of the 68-kDa gelatinase A activation intermediate to the fully active 66-kDa enzyme by concanavalin A-stimulated cells. The MT1-MMP hemopexin C domain did not form homodimers nor did it bind the gelatinase A hemopexin C domain, the C tail of TIMP-2, or full-length TIMP-2. Hence, the ectodomain of the remnant 44-kDa form of MT1-MMP appears to play little if any role in the activation of gelatinase A favoring the hypothesis that it accumulates on the cell surface as an inactive, stable degradation product.

Ethnocultural differences in sleep complaints among adolescents.

Data from a school survey (N = 5423) were used to examine differences in sleep complaints among adolescents from nine ethnocultural groups. Compared with Anglo youths, Chinese American youths were at significantly lower risk for insomnia, whereas Mexican American youths had an elevated risk, adjusting for the effects of age, gender, and socioeconomic status. Adjusting for the same three covariates, African, Mexican and Central American youths were at elevated risk for hypersomnia. No group was at lower risk for hypersomnia than the Anglos. The results suggest minority status may affect risk for sleep problems but that the direction and the magnitude of the effects vary depending on the outcome examined, severity of the problem, and the ethnic group studied. Given the paucity of data on culture and risk for disturbed sleep among adolescents, more research is needed on the role of ethnocultural background on sleep.

Matrix metalloproteinase-9 in myeloid cells: implications for allergic inflammation.

Matrix metalloproteinase-9 (MMP-9; 92 kDa gelatinase) is utilized by myeloid and lymphoid cells for migration across basement membranes. Although eosinophils are commonly seen infiltrating asthmatic airways, the role of basophils in allergic inflammation is debated. This study was undertaken to evaluate the content of MMP-9 in purified basophils compared with eosinophils and neutrophils. Peripheral blood basophils were isolated to greater than 95% purity using negative selection with antibody-coated magnetic beads using a 12-antibody cocktail. Eosinophils of greater than 98% purity were obtained by negative selection and neutrophils by positive selection using anti-CD16 magnetic beads. MMP-9 activity was assessed by gelatin zymography of cell lysates. Under parallel conditions, neutrophils contained 1,000-fold more MMP-9 than eosinophils. No activity was detected from 2x10(5) basophils. Immunocytochemistry with an anti-MMP-9 antibody showed bright staining of all neutrophils, lesser staining of eosinophils and no detectable staining of basophils. The failure to find MMP-9 in basophils may explain their paucity in asthmatic airway inflammation or suggest they secrete other enzymes capable of degrading type IV collagen.

Phlebotomine sand fly (Diptera: Psychodidae) seasonal distribution and infection rates in a defined focus of Leishmania tropica.

A two-year study was conducted of phlebotomine sand fly fauna in a defined focus of Leishmania tropica. A total of 17,947 sand flies representing 10 species were collected from the location. Phlebotomus guggisbergi, a vector of L. tropica in Kenya, was the most prevalent species through the entire period, representing about 80% of the total catch. There was marked seasonal fluctuation in the populations of the three most common species, with highest population levels reached in December and lowest levels reached in July and August. Leishmania-like infections were encountered in 489 P. guggisbergi. No flagellate infections were observed in any other species of sand fly. Although infected P. guggisbergi were collected during each month of the year, the percent parous infected flies was highest (27.5%) during the November through January time period. These data show that the greatest risk of transmission to humans at this focus occurs during December, when the vector is prevalent and infections are common.

Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model.

OBJECTIVE: To investigate the effects of retrovirus-based gene delivery of inhibitory cytokines and cytokine inhibitors into human synovial fibroblasts in the SCID mouse model of rheumatoid arthritis (RA). METHODS: The MFG vector was used for gene delivery of tumor necrosis factor alpha receptor (TNFalphaR) p55, viral interleukin-10 (IL-10), and murine IL-10 into RA synovial fibroblasts. The effect on invasion of these cells into human articular cartilage and on perichondrocytic cartilage degradation was examined after 60 days of coimplantation into the SCID mouse. RESULTS: TNFalphaR p55 gene transfer showed only a limited effect on inhibition of RA synovial fibroblast invasiveness and cartilage degradation. In contrast, invasion of the RA synovial fibroblasts into the coimplanted cartilage was strongly inhibited by both viral and murine IL-10. Perichondrocytic cartilage degradation was not affected by either form of IL-10. CONCLUSION: The data show that cytokines can be successfully inserted into the genome of human RA synovial fibroblasts using a retroviral vector delivery system, and that the SCID mouse model of human RA is a valuable tool for examining the effects of gene transfer. In addition, inhibition of more than one cytokine pathway may be required to inhibit both synovial- and chondrocyte-mediated cartilage destruction in RA.

Suicidal thinking among adolescents with a history of attempted suicide.

OBJECTIVE: To examine the risk of suicidal plans and ideation, depression, and other factors (low self-esteem, loneliness, fatalism, pessimism) among adolescents with a lifetime history of attempted suicide. METHOD: A self-administered questionnaire was used in a school-based survey of five middle schools (grades 6 through 8) enrolling 6,400 students. Usable questionnaires were obtained from 5,423 (85.3%). Data were obtained on a wide range of constructs including recent and lifetime suicide attempts, recent and lifetime suicide plans, recent ideation, symptoms of DSM-IV major depression, self-esteem, pessimism, loneliness, and fatalism. RESULTS: Data on crude prevalence showed thoughts about death, wishing to be dead, thoughts of suicide, and suicide plans were all significantly higher among youths with a history of attempts. Suicidal thinking was related to being more lonely, more fatalistic, and more pessimistic, and to less self-esteem, in addition to depression and a history of attempts. Multivariate analyses revealed the strongest factors associated with current suicidal thinking were history of attempts (odds ratio [OR] = 3.50), depression (OR = 5.34), and recent life stress (OR = 2.64). Compared with youths with none of the factors examined, those with six or more were at extreme risk (OR = 67.87). CONCLUSIONS: The strong association between history of suicide attempts, current ideation, and depression indicates that past suicide attempts occur in the context of other signs of psychosocial dysfunction. Given the paucity of epidemiological data on the natural history of suicidal behaviors among youths, more epidemiological studies of the antecedents and consequences of the range of suicidal behaviors among children and adolescents are needed. Given the high risk of subsequent suicidal behaviors by youths who have attempted but not completed suicide, this constitutes a high-risk population on which future research should focus.

Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma.

The tight-skin (Tsk/+) mutant mouse, a putative murine model of scleroderma, is characterized primarily by the excessive deposition of collagen and other extracellular matrix molecules in the dermis, and also by a developmentally acquired defect in pulmonary architecture. Passive transfer experiments have suggested an etiologic role for the immune system in Tsk/+ dermal pathology. In addition, CD4+ T lymphocytes have been shown to be required for the excessive accumulation of dermal collagen in these mice. As IL-4, a product of differentiated CD4+ T cells, is capable of regulating the synthesis of various matrix molecules (including type I collagen) by fibroblasts in vitro, we investigated the potential role of IL-4 in mediating Tsk/+ dermal fibrosis. Confirming that Tsk/+ cells are capable of responding to IL-4, we found receptors for this cytokine on Tsk/+ embryonic fibroblasts and a dermal fibroblast cell line derived from these mice. Furthermore, IL-4 receptors on Tsk/+ fibroblasts were functional since IL-4 stimulation in vitro increased type I collagen secretion from these cells. These results demonstrated the potential for IL-4 to be directly involved in the excessive deposition of dermal collagen in Tsk/+ mice. Critical insight into the role played by IL-4 in mediating the dermal phenotype, however, was obtained following the administration of neutralizing anti-lL-4 antibodies to Tsk/+ mice. This treatment prevented the development of dermal fibrosis, leading to normalization of dermal collagen content. Given the requirement for CD4+ T cells in Tsk/+ dermal fibrosis, our results suggest that Th2 cells and/or factors elaborated by this T cell subset may play a key role in regulating dermal collagen content in this strain.

Role of factor V Leiden mutation in patients with angiographically demonstrated coronary artery disease.

The study sought to determine whether coagulation factor V Leiden (FV Leiden) plays a role in the pathogenesis of coronary artery disease and/or myocardial infarction. Association of FV Leiden with venous thromboembolism is well established in the literature, but the role of the mutation in arterial thrombotic events is controversial. Some studies have documented an association between the mutation and myocardial infarction and stroke in juveniles. Few studies have explored its possible contribution to coronary atherosclerosis. We screened FV genotype in 850 predominantly white coronary angiography patients. Coronary artery disease risk factors and history of myocardial infarction were then analyzed by genotype. The FV Leiden mutation occurred in 54 (6.4%) patients. There was one homozygote; a 37-year-old, white male smoker with a history of myocardial infarction. Gene frequencies for white males and females were similar: 0.965 for the normal allele and 0.035 for FV Leiden. Gene frequencies for both genders were in Hardy-Weinberg equilibrium. FV Leiden was not a useful predictor (p=0.23) of the presence of clinically defined atherosclerosis (> or = 50% stenosis) in a logistic regression model adjusting for age, lipoprotein (a), total cholesterol, triglycerides, high density lipoprotein cholesterol, and fibrinogen. In addition, there was no difference in frequency of FV Leiden among those with and without medical histories of myocardial infarction (p=0.51). Allelic frequencies of FV Leiden in this patient group do not differ significantly from those reported for white populations. The FV Leiden mutation in its heterozygous state is not independently associated with coronary artery disease or myocardial infarction.

Ultrastructure and tensile properties of human tracheal cartilage.

The cartilage of the walls of the trachea and bronchi acts to keep these airways open despite intrathoracic pressure differences during breathing that would otherwise collapse them and limit air flow. Changes in biomechanical properties and composition of airway cartilage may contribute to altered lung function in obstructive lung diseases. To investigate the relationship between collagen organization and equilibrium tensile modulus within the structure of airway cartilage, we used scanning electron microscopy (SEM), histochemistry and equilibrium tensile testing to analyze tracheal cartilage from 10 humans aged 17-81 yr. We show that the surfaces of tracheal cartilage matrix are collagen-rich and surround a proteoglycan-rich core. Collagen fibrils in the superficial zones are oriented in the plane of the cartilage surface. In deeper layers of the cartilage, collagen fibrils are oriented less regularly. Equilibrium tensile modulus of 100 microm thick strips of cartilage was measured and was found to decrease with depth; from 13.6 +/- 1.5 MPa for the ablumenal superficial zone to 4.6 +/- 1.7 MPa in the middle zone (means +/- S.D., n = 10, p < 0.001). Stress-strain curves were linear for strains up to 10% with minimal residual strain. This is consistent with a model in which collagen fibres in the outer layers of the cartilage resist tensile forces, and hydrated proteoglycans in the central zone resist compression forces as the cartilage crescent bends.

Ethnocultural differences in prevalence of adolescent suicidal behaviors.

Data from an ethnically diverse sample of middle school students (grades 6-8; n = 5,423) are analyzed for ethnic differences in suicidal ideation, thoughts about suicide in the past 2 weeks, suicide plans, and suicide attempts. Ideation was examined using a four-item scale and a single item on suicidal thoughts. Ideation was higher among females, older youths, and lower status youths. The same general pattern held for recent suicidal plans and attempts, with the exception of gender, where the trend was for males to report more attempts. Lifetime plans and attempts were higher for females, older youths, and lower status youths. Data were sufficient to compare nine ethnic groups. Multivariate logistic regression analyses, adjusting for the effects of age, gender, and socioeconomic status, yielded significant odds ratios using the Anglo groups as the reference, for suicidal ideation for the Mexican (OR = 1.76, p < .001), Pakistani (OR = 2.0, p < .01), and Vietnamese (OR = 1.48, p < .05) American groups. For thoughts about suicide in the past 2 weeks, only Pakistani and Mixed Ancestry youths had elevated risk. For suicidal plans in the past 2 weeks, Mixed Ancestry youths (OR = 2.02, p < .05) and Pakistani youths (OR = 3.20, p < .01) had elevated risk. For recent attempts, only the Pakistani American youths had elevated risk (OR = 3.19, p < .01). Future research needs to address whether these results hold in other ethnically diverse communities and, if so, what factors contribute to increased risk among some minority youth and not others.

Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective.

Rheumatoid arthritis (RA) is characterized by progressive destruction of synovial cartilage. In vitro, degradation of cartilage is stimulated by IL-1, a proinflammatory cytokine, which is released from RA synovial fibroblasts (RA-SF). To determine whether gene therapy using the gene encoding the naturally occurring inhibitor of IL-1, IL-1 receptor antagonist (IL-1Ra) is feasible, IL-1 Ra-transduced RA-SF were coimplanted with normal human cartilage in SCID mice. The IL-1 Ra-transduced RA-SF continued to secrete IL-1Ra over a 60-day period. Cartilage that was coimplanted with RA-SF transduced with a marker gene exhibited progressive, chondrocyte-mediated cartilage degradation, whereas no such degradation was observed in cartilage that was coimplanted with RA-SF transduced with IL-1 Ra. Thus, gene therapy using a retrovirus-based gene delivery system appears to be a feasible approach to effectively modifying the local synovial environment.

Ethnocultural differences in prevalence of adolescent depression.

Data from an ethnically diverse sample of middle school (Grades 6-8) students (n = 5,423) are analyzed for ethnic differences in major depression. The point prevalence of major depression was 8.4% without and 4.3% with impairment. Data were sufficient to calculate prevalences for nine ethnic groups. Prevalences adjusted for impairment ranged from 1.9% for youths of Chinese descent to 6.6% for those of Mexican decent. African and Mexican American youths had significantly higher crude rates of depression without impairment, but only the latter had significantly higher rates of depression with impairment. Multivariate (logistic regression) analyses, adjusting for the effects of age, gender, and socioeconomic status (SES), yielded significant odds ratios for only one group. Mexican American youths were at elevated risk for both depression without (OR = 1.74, p < .05) and depression with impairment (OR = 1.71, p < .05). There was no significant interaction of ethnicity and SES in relation to depression. Females had higher prevalences of depression with and without impairment, as did youths who reported that their SES was somewhat or much worse off than their peers. The data add to growing evidence that Mexican American youths are at increased risk of depression, and that community intervention efforts should specifically target this high-risk group.