Monitoring quality and coverage of harm reduction services for people who use drugs: a consensus study.

BACKGROUND AND AIMS: Despite advances in our knowledge of effective services for people who use drugs over the last decades globally, coverage remains poor in most countries, while quality is often unknown. This paper aims to discuss the historical development of successful epidemiological indicators and to present a framework for extending them with additional indicators of coverage and quality of harm reduction services, for monitoring and evaluation at international, national or subnational levels. The ultimate aim is to improve these services in order to reduce health and social problems among people who use drugs, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection, crime and legal problems, overdose (death) and other morbidity and mortality. METHODS AND RESULTS: The framework was developed collaboratively using consensus methods involving nominal group meetings, review of existing quality standards, repeated email commenting rounds and qualitative analysis of opinions/experiences from a broad range of professionals/experts, including members of civil society and organisations representing people who use drugs. Twelve priority candidate indicators are proposed for opioid agonist therapy (OAT), needle and syringe programmes (NSP) and generic cross-cutting aspects of harm reduction (and potentially other drug) services. Under the specific OAT indicators, priority indicators included 'coverage', 'waiting list time', 'dosage' and 'availability in prisons'. For the specific NSP indicators, the priority indicators included 'coverage', 'number of needles/syringes distributed/collected', 'provision of other drug use paraphernalia' and 'availability in prisons'. Among the generic or cross-cutting indicators the priority indicators were 'infectious diseases counselling and care', 'take away naloxone', 'information on safe use/sex' and 'condoms'. We discuss conditions for the successful development of the suggested indicators and constraints (e.g. funding, ideology). We propose conducting a pilot study to test the feasibility and applicability of the proposed indicators before their scaling up and routine implementation, to evaluate their effectiveness in comparing service coverage and quality across countries. CONCLUSIONS: The establishment of an improved set of validated and internationally agreed upon best practice indicators for monitoring harm reduction service will provide a structural basis for public health and epidemiological studies and support evidence and human rights-based health policies, services and interventions.

Lethality of Opioid Overdose in a Community Cohort of Young Heroin Users.

BACKGROUND: The aim of the study was to estimate the lethality of opioid overdose among young heroin users. METHODS: A prospective community cohort study was conducted in Barcelona and Madrid, Spain. Participants included 791 heroin users aged 18-30 years who were followed up between 2001 and 2006. Fatal overdoses were identified by record linkage of the cohort with the general mortality register, while non-fatal overdoses were self-reported at baseline and follow-up interviews. The person-years (py) at risk were computed for each participant. Fatal and non-fatal overdose rates were estimated by city. Transition towards injection shortly before the overdose could not be measured. Overdose lethality (rate of fatal overdose in proportion to total overdose) and its 95% CI was estimated using Bayesian models. RESULTS: The adjusted rates of fatal and non-fatal opioid overdose were 0.7/100 py (95% CI: 0.4-1.1) and 15.8/100 py (95% CI: 14.3-17.6), respectively. The adjusted lethality was 4.2% (95% CI: 2.5-6.5). CONCLUSIONS: Four out of 100 opioid overdoses are fatal. These are preventable deaths that could be avoided before or after the overdose takes place. Resources are urgently needed to prevent fatal opioid overdose.

Differences in illegal drug consumption between native and immigrants in a large sample of injected drug users in Catalonia (Spain).

The aims of this study were to describe illegal drug abuse patterns in relation to the migration process and use of drug treatment centers among immigrant injected drug users (IDUs) involved in harm reduction programs, and to compare the characteristics of immigrant and native IDUs. Cross-sectional study of 748 IDUs aged ≥18 years attending harm reduction centers between 2008 and 2009. We explored differences in socio-economic status, illegal drug consumption, health status and use of treatment centers in native versus immigrant IDUs. We also described whether immigrant IDUs started using injected drugs before or after entering the host country. Immigrant IDUs tend to live alone more frequently, start injection at later ages, use heroin and inject it more frequently and use drug treatment centers less frequently than native IDUs. Seventy-six percent of immigrants began using illegal drugs before arriving at the host country. Those who started in other countries were residing in the host country for 5 years or less (63.9%). Overall, immigrant IDUs attended drug treatment centers (36.9%) less frequently than native IDUs (71.8%). In conclusion, migration could be a risk factor for illegal drug abuse initiation or increase in consumption, often with the adoption of local consumption patterns and aggravated due to a lower access to drug treatment centers.

Improved reconstructions and generalized filtered back projection for optical projection tomography.

Optical projection tomography (OPT) is a noninvasive imaging technique that enables imaging of small specimens (<1 cm), such as organs or animals in early developmental stages. In this paper, we present a set of computational methods that can be applied to the acquired data sets in order to correct for (a) unknown background or illumination intensity distributions over the field of view, (b) intensity spikes in single CCD pixels (so-called "hot pixels"), and (c) refractive index mismatch between the media in which the specimens are embedded and the environment. We have tested these correction methods using a variety of samples and present results obtained from Parhyale hawaiensis embedded in glycerol and in sea water. Successful reconstructions of fluorescence and absorption OPT images have been obtained for weakly scattering specimens embedded in media with nonmatched refractive index, thus advancing OPT toward routine in vivo imaging.

Source intensity profile in noncontact optical tomography.

Noncontact optical tomography in reflection mode is often the only possible configuration when imaging the expression of green fluorescent protein (GFP) or other fluorescent proteins in live animals owing to the short penetration depth of visible light. When imaging in reflection mode using noncontact approaches (i.e., without the use of fibers coupled to tissue), correctly accounting for the intensity profile of the source at the surface is a difficult task, usually needing to fit for source positions and/or approximating these to point sources. In this Letter we present a rigorous theoretical approach that directly accounts for the source's intensity profile and verify it using in vivo data from GFP-expressing mice. We show how this approach improves image quality and resolution, while considerably simplifying the forward and inverse problems of the image reconstruction process.

Tenascin-C induction by cyclic strain requires integrin-linked kinase.

Induction of tenascin-C mRNA by cyclic strain in fibroblasts depends on RhoA and Rho dependent kinase (ROCK). Here we show that integrin-linked kinase (ILK) is required upstream of this pathway. In ILK-deficient fibroblasts, RhoA was not activated and tenascin-C mRNA remained low after cyclic strain; tenascin-C expression was unaffected by ROCK inhibition. In ILK wild-type but not ILK-/- fibroblasts, cyclic strain-induced reorganization of actin stress fibers and focal adhesions, as well as nuclear translocation of MAL, a transcriptional co-activator that links actin assembly to gene expression. These findings support a role for RhoA in ILK-mediated mechanotransduction. Rescue of ILK -/- fibroblasts by expression of wild-type ILK restored these responses to cyclic strain. Mechanosensation is not entirely abolished in ILK -/- fibroblasts, since cyclic strain activated Erk-1/2 and PKB/Akt, and induced c-fos mRNA in these cells. Conversely, lysophosphatidic acid stimulated RhoA and induced both c-fos and tenascin-C mRNA in ILK -/- cells. Thus, the signaling pathways controlling tenascin-C expression are functional in the absence of ILK, but are not triggered by cyclic strain. Our results indicate that ILK is selectively required for the induction of specific genes by mechanical stimulation via RhoA-mediated pathways.

Risk of stroke in prescription and other amphetamine-type stimulants use: A systematic review.

INTRODUCTION AND AIMS: Amphetamine-type stimulants (ATS) are a putative cause of stroke with high abuse potential. We aim to systematically review the association between use of ATS and stroke. DESIGN AND METHODS: To assure a sensitive search strategy, a broad definition of ATS was used. Cochrane Plus, EMBASE, IBECS/Lilacs, ISI WOK, Medline and Scopus were searched through 2016. Three researchers independently reviewed studies (Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-analyses). Validity and bias were appraised. RESULTS: Of 3998 articles, four cohort studies and eight case-control studies (CCS) were selected; 11 focused on prescribed or over-the-counter ATS. Current ATS users showed a higher ischaemic stroke risk than non-users in two cohort studies {adjusted rate ratio = 1.6 [95% confidence interval (CI) = 1.1, 2.4] and 3.4 [95% CI = 1.1, 10.6]}. One study observed increased risk of haemorrhagic stroke in former users versus non-users [adjusted rate ratio = 2.3 (95% CI = 1.3, 4.1)]. Higher haemorrhagic stroke risk was seen in two CCS among women using ATS [adjusted odds ratio (aOR) = 16.6 (95% CI = 1.5, 182.2) and 3.9 (95% CI = 1.1, 13.1)]. All-stroke was negatively associated with ATS in another CCS [aOR = 0.4 (95% CI = 0.2, 0.8)] and positively associated in the only study on non-medical ATS [aOR = 3.8 (95% CI = 1.2, 12.6)]. Selection bias and uncontrolled confounding were common. DISCUSSION AND CONCLUSIONS: This is the first systematic review on ATS and stroke. Limited epidemiological evidence suggests that ATS use increases stroke risk. Possible disparities in ATS effect across stroke type and higher effect in women deserve further clarification. Studies on non-medical ATS use should be a priority. [Indave BI, Sordo L, Bravo MJ, Sarasa-Renedo A, Fernández-Balbuena S, De la Fuente L, Sonego M, Barrio G. Risk of stroke in prescription and other amphetamine-type stimulants use: A systematic review. Drug Alcohol Rev 2018;37:56-69].

Differences between men and women in substance use: the role of educational level and employment status.

OBJECTIVE: To determine differences between men and women in hazardous drinking, heavy cannabis use and hypnosedative use according to educational level and employment status in the economically active population in Spain. METHOD: Cross-sectional study with data from 2013 Spanish Household Survey on Alcohol and Drugs on individuals aged 25-64 [n=14,113 (women=6,171; men=7,942)]. Dependent variables were hazardous drinking, heavy cannabis use and hypnosedative consumption; the main independent variables were educational level and employment situation. Associations between dependent and independent variables were calculated with Poisson regression models with robust variance. All analyses were stratified by sex. RESULTS: Hazardous drinking and heavy cannabis use were higher in men, while women consumed more hypnosedatives. The lower the educational level, the greater the gender differences in the prevalence of this substances owing to different consumption patterns in men and women. While men with a lower educational level were higher hazardous drinkers [RII=2.57 (95%CI: 1.75-3.78)] and heavy cannabis users [RII=3.03 (95%CI: 1.88-4.89)] compared to higher educational level, in women the prevalence was the same. Women with a lower education level and men with a higher education level had higher hypnosedative consumption. Unemployment was associated with increased heavy cannabis use and hypnosedative use in both women and men and with lower hazardous drinking only in women. CONCLUSIONS: There are differences between men and women in the use of psychoactive substances that can be explained by the unequal distribution of substance use in them according to educational level. Unemployment was associated with substance use in both men and women.

Is systematic training in opioid overdose prevention effective?

The objectives were to analyze the knowledge about overdose prevention, the use of naloxone, and the number of fatal overdoses after the implementation of Systematic Training in Overdose Prevention (STOOP) program. We conducted a quasi-experimental study, and held face-to-face interviews before (n = 725) and after (n = 722) implementation of systematic training in two different samples of people who injected opioids attending harm reduction centers. We asked participants to list the main causes of overdose and the main actions that should be taken when witnessing an overdose. We created two dependent variables, the number of (a) correct and (b) incorrect answers. The main independent variable was Study Group: Intervention Group (IG), Comparison Group (CG), Pre-Intervention Group With Sporadic Training in Overdose Prevention (PREIGS), or Pre-Intervention Group Without Training in Overdose Prevention (PREIGW). The relationship between the dependent and independent variables was assessed using a multivariate Poisson regression analysis. Finally, we conducted an interrupted time series analysis of monthly fatal overdoses before and after the implementation of systematic program during the period 2006-2015. Knowledge of overdose prevention increased after implementing systematic training program. Compared to the PREIGW, the IG gave more correct answers (IRR = 1.40;95%CI:1.33-1.47), and fewer incorrect answers (IRR = 0.33;95%CI:0.25-0.44). Forty percent of people who injected opioids who received a naloxone kit had used the kit in response to an overdose they witnessed. These courses increase knowledge of overdose prevention in people who use opioids, give them the necessary skills to use naloxone, and slightly diminish the number of fatal opioid overdoses in the city of Barcelona.

Assessing gender disparities in excess mortality of heroin or cocaine users compared to the general population.

BACKGROUND: Previous analyses of excess mortality in drug users compared with the general population have almost always been based on mortality ratios, reporting much higher figures in women than men. This study tests the hypothesis that being a heroin or cocaine user adds more death risk in women than men in Spain. METHODS: A retrospective cohort of 15,305 heroin users (HUs) and 11,905 cocaine users (CUs) aged 15-49 starting drug treatment in 1997-2007 was recruited in Spain and followed until December 2008 to determine vital status and cause of death. Excess mortality in men and women compared to the general population was assessed with directly age-standardized rate ratios (SRRs) and differences (SRDs). RESULTS: SRR was significantly higher in women than men for all causes (14.7 vs. 9.4), natural causes (8.7 vs. 6.2), overdose (331.6 vs. 163.9) and other external causes (46.9 vs. 11.8) among HUs; and for overdose (170.8 vs. 40.5) and other external causes (21.0 vs. 4.7) among CUs. However, the opposite happened with SRD for all causes (1294 vs. 1845 deaths/100,000 person-years), natural causes (675 vs. 1016 deaths/100,000 person-years) and overdose (331 vs. 619 deaths/100,000 person-years) among HUs, while no significant SRD gender disparities were observed among CUs. CONCLUSION: Compared with the general population, being a heroin user adds greater absolute risk in men than women, but this does not happen with cocaine users. Similar results would likely have been found in most published cohort studies if this indicator had been used; the exclusive use of relative indices of disparity as in previous meta-analysis can be extremely misleading.

Induction of tenascin-C by cyclic tensile strain versus growth factors: distinct contributions by Rho/ROCK and MAPK signaling pathways.

Expression of the extracellular matrix (ECM) protein tenascin-C is induced in fibroblasts by growth factors as well as by tensile strain. Mechanical stress can act on gene regulation directly, or indirectly via the paracrine release of soluble factors by the stimulated cells. To distinguish between these possibilities for tenascin-C, we asked whether cyclic tensile strain and soluble factors, respectively, induced its mRNA via related or separate mechanisms. When cyclic strain was applied to chick embryo fibroblasts cultured on silicone membranes, tenascin-C mRNA and protein levels were increased twofold within 6 h compared to the resting control. Medium conditioned by strained cells did not stimulate tenascin-C mRNA in resting cells. Tenascin-C mRNA in resting cells was increased by serum; however, cyclic strain still caused an additional induction. Likewise, the effect of TGF-beta1 or PDGF-BB was additive to that of cyclic strain, whereas IL-4 or H2O2 (a reactive oxygen species, ROS) did not change tenascin-C mRNA levels. Antagonists for distinct mitogen-activated protein kinases (MAPK) inhibited tenascin-C induction by TGF-beta1 and PDGF-BB, but not by cyclic strain. Conversely, a specific inhibitor of Rho-dependent kinase strongly attenuated the response of tenascin-C mRNA to cyclic strain, but had limited effect on induction by growth factors. The data suggest that regulation of tenascin-C in fibroblasts by cyclic strain occurs independently from soluble mediators and MAPK pathways; however, it requires Rho/ROCK signaling.

Effect of immigration background and country-of-origin contextual factors on adolescent substance use in Spain.

PURPOSE: The effects of adolescent- and parental-birthplace and country-of-origin contextual factors on substance use among adolescents with recent immigrant background (ARIBs) are poorly understood. We aimed to assess these effects and identify the main mediating factors in Spain. METHODS: Participants were 12,432 ARIBs (≥1 foreign-born parent) and 75,511 autochthonous adolescents from pooled 2006-2010 school surveys. Outcomes were prevalence of use of alcohol, tobacco, cannabis, stimulants and sedative-hypnotics. ARIBs were classified by adolescent birthplace (Spain/abroad), whether they had mixed-parents (one Spanish-born and one foreign-born), and country-of-origin characteristics. Adjusted prevalence ratios (aPRs) and percent change expressing disparities in risk were estimated using Poisson regression with robust variance. RESULTS: Compared to autochthonous adolescents, foreign-born ARIBs without mixed-parents showed significant aPRs <1 for all substances, which generally approached 1 in Spanish-born ARIBs with mixed-parents. The main factors mediating ARIBs' lower risk were less frequent socialization in leisure environments and less association with peers who use such substances. ARIBs' lower risk depended more on country-of-origin characteristics and not having mixed-parents than being foreign-born. Tobacco, cannabis and stimulant use in ARIBs increased with increasing population use of these substances in the country-of-origin. ARIBs from the non-Muslim-regions had a lower risk of using alcohol and higher risk of using sedative-hypnotics than those from the Muslim-region. CONCLUSIONS: Among ARIBs in Spain, parental transmission of norms and values could influence substance use as much as or more than exposure to the Spanish context. Future research should better assess effects of adolescent- and parental-birthplace and country-of-origin contextual factors on substance use.

[Research methods on alcohol-related harm in the population]. / Métodos de investigación sobre daños en la población relacionados con el alcohol.

The aim of this paper is to describe the available methods to quantify the main health and social harms related to alcohol consumption in the population and to provide recommendations to improve research on these issues. Methods using individual and aggregate level data for the study of the relationship between alcohol consumption and related harms are taken into account, highlighting their strengths and weaknesses. Methodological aspects to quantify the magnitude and trends of alcohol-related and alcohol-attributable mortality, including alcohol dependence, acute intoxication, injury, violent behavior, disease burden and social costs are widely considered. There are often discrepancies between the study results mainly due to the difficulty of adequately measuring alcohol consumption and its relationship to health conditions. In the future we must strengthen research on the effect of drinking patterns and context in chronic diseases using appropriate controls, clarify the relationship of alcohol use disorders and other mental disorders , improve the measurement of alcohol intoxication when acute problems occurs, periodically quantify the disease burden and social costs attributable to alcohol (using country- specific attributable fractions) and develop valid and comparable methods and indicators for monitoring alcohol-related harm.

[Health and social harm related alcohol]. / Principales daños sanitarios y sociales relacionados con el consumo de alcohol.

Alcohol affects the brain and most organs and systems, and its use is related to a large number of health problems. These include mental, neurological, digestive, cardiovascular, endocrine, metabolic, perinatal, cancerous, and infectious diseases, as well as intentional and non-intentional injuries. Physiopathological mechanisms still remain unraveled, though direct toxicity of ethanol and its metabolites, nutritional deficit and intestinal microbial endotoxin absorption have been suggested, all of which would be further modulated by use patterns and genetic and environmental factors. Individually it is difficult to precisely predict who will or will not suffer health consequences. At population level several disorders show a linear or exponential dose-response relationship, as is the case with various cancer types, hepatopathies, injuries, and probably risky behaviors such as unsafe sex. Other health problems such as general mortality in people above 45 years of age, ischemic disease or diabetes mellitus show a J-shaped relationship with alcohol use. The overall effect of alcohol on the global burden of disease is highly detrimental, despite the possible beneficial effect on cardiovascular disease. Large differences are found by country, age, gender, socioeconomic and other factors. Disease burden is mostly related with alcohol's capacity to produce dependence and with acute intoxication. Often alcohol also produces negative consequences for other people (violence, unattended family or work duties, etc) which are generally not taken into account when evaluating burden of disease. The aim of this study was to describe the main alcohol-related social and health harms, as well as their generating mechanisms, using secondary data sources.

Overdose prevention in injecting opioid users: the role of substance abuse treatment and training programs.

OBJECTIVES: Opioid overdose is still the first cause of preventable death among young men in Barcelona. Sound knowledge of opioid overdose prevention is important to avoid complications and deaths. This study aimed to identify the factors associated with limited knowledge of overdose prevention and to assess the possible effect of treatment and overdose prevention training programs on this variable. METHODS: From October 2008 to March 2009, current injecting opioid users attending harm reduction centers in Catalonia (Spain) were interviewed. Crude and adjusted prevalence ratios of limited knowledge about overdose prevention were calculated by adjusting Poisson regression models with a robust variance. RESULTS: In this sample, 28.7% of clients had limited knowledge of overdose prevention. Factors associated with limited knowledge were country of origin, never having received treatment for drug dependency, having a low educational level, and never having experienced an overdose. In contrast, treatment at the time of the interview was not associated with a lower prevalence of limited knowledge about overdose prevention. CONCLUSIONS: These findings suggest that preventive programs would benefit from accounting for linguistic and educational limitations and from participation in every treatment episode. Comprehensiveness and broad coverage of such programs could help to maximize their impact.

Correction for specimen movement and rotation errors for in-vivo Optical Projection Tomography.

The application of optical projection tomography to in-vivo experiments is limited by specimen movement during the acquisition. We present a set of mathematical correction methods applied to the acquired data stacks to correct for movement in both directions of the image plane. These methods have been applied to correct experimental data taken from in-vivo optical projection tomography experiments in Caenorhabditis elegans. Successful reconstructions for both fluorescence and white light (absorption) measurements are shown. Since no difference between movement of the animal and movement of the rotation axis is made, this approach at the same time removes artifacts due to mechanical drifts and errors in the assumed center of rotation.

Imaging changes in lymphoid organs in vivo after brain ischemia with three-dimensional fluorescence molecular tomography in transgenic mice expressing green fluorescent protein in T lymphocytes.

Stroke induces a strong inflammatory reaction in the brain and depresses the immune system. We sought to assess longitudinal changes in T-cell numbers in the lymphoid organs of living mice after brain ischemia. Middle cerebral artery occlusion was carried out in transgenic mice expressing green fluorescent protein (GFP+) in the T-cell population under the control of the hCD2 locus control region. Imaging was performed by three-dimensional fluorescence molecular tomography (FMT) before and at several time points after ischemia or sham operation and in controls. At day 7, GFP+ cell content in lymphoid organs was measured postmortem by flow cytometry. GFP+ cell numbers and in vivo FMT signal intensity were reduced at day 7 after ischemia and, to a lesser extent, after sham operation. Linear regression analysis demonstrated that postmortem GFP+ cell numbers and corresponding in vivo FMT data were significantly correlated in the thymus (r2 = .65, p < .0001) and lymph nodes (r2 = .67, p < .0001). These relationships allowed inferring the number of GFP+ T cells from in vivo FMT data. The results show the time course reduction of T-cell content in the lymphoid organs of living mice, providing in vivo evidence of lymphoid organ atrophy after stroke and, to a lesser extent, after head surgery with craniectomy and dura mater opening in sham-operated mice.

Gene regulation by mechanotransduction in fibroblasts.

Mechanical forces are important for connective tissue homeostasis. How do fibroblasts sense mechanical stress and how do they translate this information into an adaptive remodeling of the extracellular matrix (ECM)? Tenascin-C is rapidly induced in vivo by loading muscles and in vitro by stretching fibroblasts. Regulation of tenascin-C expression by mechanical signals occurs at the transcriptional level. Integrin receptors physically link the ECM to the cytoskeleton and act as force transducers: intracellular signals are triggered when integrins engage with ECM, and later when forces are applied. We found that cyclic strain does not induce tenascin-C messenger ribonucleic acid (mRNA) in fibroblasts lacking the beta1-integrin chain. An important link in integrin-dependent mechanotransduction is the small guanosine 5'-triphosphatase. RhoA and its target kinase, ROCK. In fibroblasts, cyclic strain activates RhoA and thereby induces ROCK-dependent actin assembly. Interestingly, tenascin-C mRNA induction by cyclic strain was suppressed by relaxing the cytoskeleton with a ROCK inhibitor or by actin depolymerization. Conversely, chemical activators of RhoA enhanced the effect of strain both on actin dynamics and on tenascin-C expression. Thus, RhoA/ROCK-controlled actin dynamics are required for the induction of specific ECM genes by mechanical stress. These findings have implications for the understanding of regeneration and for tissue engineering.

Role of RhoA/ROCK-dependent actin contractility in the induction of tenascin-C by cyclic tensile strain.

In chick embryo fibroblasts, the mRNA for extracellular matrix protein tenascin-C is induced 2-fold by cyclic strain (10%, 0.3 Hz, 6 h). This response is attenuated by inhibiting Rho-dependent kinase (ROCK). The RhoA/ROCK signaling pathway is primarily involved in actin dynamics. Here, we demonstrate its crucial importance in regulating tenascin-C expression. Cyclic strain stimulated RhoA activation and induced fibroblast contraction. Chemical activators of RhoA synergistically enhanced the effects of cyclic strain on cell contractility. Interestingly, tenascin-C mRNA levels perfectly matched the extent of RhoA/ROCK-mediated actin contraction. First, RhoA activation by thrombin, lysophosphatidic acid, or colchicine induced tenascin-C mRNA to a similar extent as strain. Second, RhoA activating drugs in combination with cyclic strain caused a super-induction (4- to 5-fold) of tenascin-C mRNA, which was again suppressed by ROCK inhibition. Third, disruption of the actin cytoskeleton with latrunculin A abolished induction of tenascin-C mRNA by chemical RhoA activators in combination with cyclic strain. Lastly, we found that myosin II activity is required for tenascin-C induction by cyclic strain. We conclude that RhoA/ROCK-controlled actin contractility has a mechanosensory function in fibroblasts that correlates directly with tenascin-C gene expression. Previous RhoA/ROCK activation, either by chemical or mechanical signals, might render fibroblasts more sensitive to external tensile stress, e.g., during wound healing.