Comparative Effectiveness of Lifestyle Intervention on Fasting Plasma Glucose in Normal Weight Versus Overweight and Obese Adults With Prediabetes.

Background. It is hypothesized that normal weight individuals develop diabetes through different pathophysiological mechanisms and that methods of prevention may differ in the absence of overweight/obesity. In this study, we compared the effect of lifestyle health coaching (LHC) on fasting plasma glucose (FPG) in normal weight, overweight, and obese US adults with prediabetes. Methods. Subjects were 1358 individuals who completed baseline and follow-up evaluations as part of an LHC program (follow-up = ~6 months). Participants were stratified, based on baseline body mass index (BMI), into normal weight (n = 129), overweight (n = 345), and obese (n = 884) cohorts. LHC included counseling, predominantly via telehealth, on exercise and nutrition. Results. BMI decreased (P < .001) in the overweight and obese participants but was unchanged in the normal weight participants. FPG decreased (P < .001) in all 3 cohorts, and the magnitude of decrease did not differ significantly among cohorts. FPG decreased to <5.6 mmol/L in 58.1%, 49.3%, and 41.4% of the normal weight, overweight, and obese participants, respectively. Conclusions. To our knowledge, this study is the first outside of Asia to show that LHC is as effective in managing FPG in normal weight adults with prediabetes versus those who are overweight/obese.

The neurology-psychiatry interface in epilepsy.

Epilepsy and mental illness have a bidirectional association. Psychiatrists are likely to encounter epilepsy as comorbidity. Seizures may present as mental illness. Equally, the management of psychiatric conditions has the potential to destabilise epilepsy. There is a need for structured epilepsy awareness and training amongst psychiatrists. This paper outlines key considerations around diagnosis, treatment and risk while suggesting practical recommendations.

A tool to evaluate proportionality and necessity in the use of restrictive practices in forensic mental health settings: the DRILL tool (Dundrum restriction, intrusion and liberty ladders).

BACKGROUND: Prevention of violence due to severe mental disorders in psychiatric hospitals may require intrusive, restrictive and coercive therapeutic practices. Research concerning appropriate use of such interventions is limited by lack of a system for description and measurement. We set out to devise and validate a tool for clinicians and secure hospitals to assess necessity and proportionality between imminent violence and restrictive practices including de-escalation, seclusion, restraint, forced medication and others. METHODS: In this retrospective observational cohort study, 28 patients on a 12 bed male admissions unit in a secure psychiatric hospital were assessed daily for six months. Data on adverse incidents were collected from case notes, incident registers and legal registers. Using the functional assessment sequence of antecedents, behaviours and consequences (A, B, C) we devised and applied a multivariate framework of structured professional assessment tools, common adverse incidents and preventive clinical interventions to develop a tool to analyse clinical practice. We validated by testing assumptions regarding the use of restrictive and intrusive practices in the prevention of violence in hospital. We aimed to provide a system for measuring contextual and individual factors contributing to adverse events and to assess whether the measured seriousness of threating and violent behaviours is proportionate to the degree of restrictive interventions used. General Estimating Equations tested preliminary models of contexts, decisions and pathways to interventions. RESULTS: A system for measuring adverse behaviours and restrictive, intrusive interventions for prevention had good internal consistency. Interventions were proportionate to seriousness of harmful behaviours. A 'Pareto' group of patients (5/28) were responsible for the majority (80%) of adverse events, outcomes and interventions. The seriousness of the precipitating events correlated with the degree of restrictions utilised to safely manage or treat such behaviours. CONCLUSION: Observational scales can be used for restrictive, intrusive or coercive practices in psychiatry even though these involve interrelated complex sequences of interactions. The DRILL tool has been validated to assess the necessity and demonstrate proportionality of restrictive practices. This tool will be of benefit to services when reviewing practices internally, for mandatory external reviewing bodies and for future clinical research paradigms.

Dietary Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) Operate by Different Mechanisms to Modulate Hepatic Steatosis and Hyperinsulemia in fa/fa Zucker Rats.

Hepatic steatosis, an early stage of non-alcoholic fatty liver disease, is commonly present in obesity and type 2 diabetes, and is associated with reduced hepatic omega-3 polyunsaturated fatty acid (n3-PUFA) status that impacts on the anti-inflammatory and insulin sensitizing functions of n3-PUFA. Our objective was to directly compare plant- and marine-based n3-PUFA (α-linoleic acid (ALA)), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) for their effects on hepatic steatosis, markers of hepatic inflammation and fibrosis, and insulinemia in obese rats. Fa/fa Zucker rats were provided diets containing ALA, EPA, DHA, or linoleic acid (LA, n6-PUFA) for eight weeks and compared to baseline fa/fa rats and lean Zucker rats fed LA-rich diet for eight weeks. Both DHA and EPA groups had liver lipid similar to baseline, however, DHA was more effective than EPA for reducing hepatic fatty acid synthase (FAS), increasing the proportion of smaller lipid droplets, reversing early fibrotic damage, and reducing fasting hyperinsulinemia. EPA was more effective for reducing FoxO1. Dietary ALA did not attenuate hepatic steatosis, most inflammatory markers or FAS. In summary, amongst the n3-PUFA, DHA was the most effective for elevating hepatic DHA levels, and preventing progression of hepatic steatosis via reductions in FAS and a marker of fibrosis.

Clinical Effectiveness of Lifestyle Health Coaching: Case Study of an Evidence-Based Program.

We have developed, tested, and successfully implemented an affordable, evidence-based, technology-enabled, data-driven, outcomes-oriented, comprehensive lifestyle health coaching (LHC) program. The LHC program has been used primarily to provide services to employees of larger employers (ie, with at least 3000 employees) but has also been implemented in a variety of other settings, including hospitals, cardiac rehabilitation centers, physician practices, and as part of multicenter clinical trials. The program is delivered mainly using the telephone and Internet. Health coaches are guided by a Web-based participant management and tracking system. Lifestyle management interventions are based on several behavior change models and strategies, especially adult learning theory, social learning theory, the stages of change model, single concept learning theory, and motivational interviewing. The program is administered by nonphysician health professionals whose services are integrated with the care provided by participants' physicians. Outcomes data from published studies, including randomized clinical trials and independent third-party conducted research, have documented the clinical effectiveness of this evidence-based approach in terms of modification of multiple risk factors in healthy persons as well as those with certain common chronic diseases.

Multicenter Study of Temporal Trends in the Achievement of Atherosclerotic Cardiovascular Disease Risk Factor Goals During Cardiac Rehabilitation.

PURPOSE: Secondary prevention risk factor goals have been established by the American Heart Association/American College of Cardiology, and the American Heart Association has further delineated ideal cardiovascular health metrics. We evaluated risk factor goal achievement during early-outpatient cardiac rehabilitation (CR) and temporal trends in risk factor control. METHODS: Patients completed assessments on entry into and exit from CR at 35 centers between 2000 and 2009 and were categorized into 3 cohorts: entire (N = 12 984), 2000-2004 (n = 5468), and 2005-2009 (n = 7516) cohorts. RESULTS: Improvements occurred in multiple risk factors during CR. For the entire cohort, the percentages of patients at goal at CR completion ranged from 95.5% for smoking to 21.9% for body mass index (BMI) of <25.0 kg/m. Compared with 2000-2004, the percentage of the 2005-2009 cohort at goal was higher (P < .001) for blood pressure, low-density lipoprotein cholesterol, and physical activity, lower (P = .005) for BMI, and not significantly different (P > .05) for fasting glucose and smoking. At CR completion, of those in the entire, 2000-2004, and 2005-2009 cohorts, 4.4%, 3.9%, and 4.8% (P = .219 vs 2000-2004), respectively, had all biomarkers at the goal for ideal cardiovascular health and, of those with atherosclerotic cardiovascular disease, 70.8%, 71.5%, and 70.3% (P = .165 vs 2000-2004), respectively, were receiving statins. CONCLUSIONS: The percentage of patients at goal at CR completion increased for some, but not all, risk factors during 2005-2009 versus 2000-2004. Despite the benefits of CR, risk factor profiles are often suboptimal after CR. There remains room for improvement in risk factor management during CR and a need for continued intervention thereafter.

Daily non-soy legume consumption reverses vascular impairment due to peripheral artery disease.

OBJECTIVE: Peripheral artery disease (PAD) results from a decrease in blood flow to the limbs due to the presence of atherosclerotic plaque. It has been reported that isoflavones isolated from soybeans reduce arterial stiffness, a component of atherosclerotic disease. This study examined the effect of consuming whole legumes (non-soy) on arterial function in humans with PAD. METHODS: Twenty-six individuals with PAD consumed ½ cup/day cooked legumes (beans, peas, lentils, chickpeas) daily for 8 weeks. Measurements of circulating factors and vascular function at baseline and study conclusion were compared. RESULTS: No changes in were detected relative to baseline values for most parameters. Total and LDL-cholesterol were reduced by 5.0% and 8.7%, respectively. The ankle-brachial index (ABI) showed a 5.5% increase. Changes in ABI and LDL-cholesterol did not correlate. Serum markers of endothelial dysfunction and inflammation were unchanged, but short-chain acylcarnitine concentrations were significantly decreased. CONCLUSIONS: A legume-rich diet can elicit major improvements in arterial function and serum cholesterol in the absence of changes in either body mass or blood pressure, although the improvements in vascular function and serum lipids were unrelated. Although the positive results obtained with this dietary intervention were not explained by biomarkers of endothelial function and inflammation, altered acylcarnitine levels indicate an improvement in skeletal muscle metabolism due to enhanced tissue perfusion.

Prospective study of factors influencing conditional discharge from a forensic hospital: the DUNDRUM-3 programme completion and DUNDRUM-4 recovery structured professional judgement instruments and risk.

BACKGROUND: We set out to examine whether structured professional judgement instruments DUNDRUM-3 programme completion (D-3) and DUNDRUM-4 recovery (D-4) scales along with measures of risk, mental state and global function could distinguish between those forensic patients detained in a secure forensic hospital (not guilty by reason of insanity or unfit to stand trial) who were subsequently discharged by a mental health review board. We also examined the interaction between these measures and risk, need for therapeutic security and eventual conditional discharge. METHODS: A naturalistic observational cohort study was carried out for 56 patients newly eligible for conditional discharge. Patients were rated using the D-3, D-4 and other scales including HCR-20, S-RAMM, START, SAPROF, PANSS and GAF and then observed over a period of twenty three months during which they were considered for conditional discharge by an independent Mental Health Review Board. RESULTS: The D-3 distinguished which patients were subsequently discharged by the Mental Health Review board (AUC = 0.902, p < 0.001) as did the D-4 (AUC = 0.848, p < 0.001). Item to outcome analysis showed each item of the D-3 and D-4 scales performed significantly better than random. The HCR-20 also distinguished those later discharged (AUC = 0.838, p < 0.001) as did the S-RAMM, START, SAPROF, PANSS and GAF. The D-3 and D-4 scores remained significantly lower (better) for those discharged even when corrected for the HCR-20 total score. Item to outcome analyses and logistic regression analysis showed that the strongest antecedents of discharge were the GAF and the DUNDRUM-3 programme completion scores. CONCLUSIONS: Structured professional judgement instruments should improve the quality, consistency and transparency of clinical recommendations and decision making at mental health review boards. Further research is required to determine whether the DUNDRUM-3 programme completion and DUNDRUM-4 recovery instruments predict those who are or are not recalled or re-offend after conditional discharge.

Effect of exercise-based cardiac rehabilitation on multiple atherosclerotic risk factors in patients taking antidepressant medication.

Antidepressants might increase compliance with cardiovascular disease risk reduction interventions. However, antidepressants have been linked to deleterious metabolic effects. In the present multicenter study, we sought to determine whether patients who take antidepressants derive the expected benefits from cardiac rehabilitation in terms of improvements in multiple atherosclerotic risk factors. A cohort of 26,957 patients who had completed a baseline assessment before participating in an exercise-based cardiac rehabilitation program constituted the study population. The patients were stratified into 3 cohorts (i.e., nondepressed, depressed unmedicated, and depressed medicated) at baseline according to a self-reported history of depression and the current use of antidepressants. Risk factors were assessed at baseline and after ∼12 weeks of program participation. A self-reported history of depression was present at baseline in 5,172 patients (19.2%). Of these patients, 2,147 (41.5%) were taking antidepressants. Patients in the nondepressed cohort (49.4% completion) were more likely (p <0.001) to complete the exit assessment than patients in the depressed unmedicated (44.5% completion) or depressed medicated (43.5% completion) cohorts. Patients in all 3 cohorts who completed the exit assessment showed significant improvement in multiple risk factors. Moreover, the magnitude of improvement in blood pressure, serum lipids and lipoproteins, fasting glucose, weight, and body mass index was similar (p >0.05) in patients taking antidepressants and those who were not. In conclusion, our study is the first to show that antidepressants do not offset the average magnitude of improvement in multiple atherosclerotic risk factors that occurs with completion of a cardiac rehabilitation program.

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form.

Accelerated atherosclerosis is the primary cardiovascular manifestation of diabetes and correlates inversely with levels of circulating adiponectin, an anti-atherosclerotic adipokine that declines in diabetes. We therefore initiated a study to examine the mechanisms by which adiponectin, a hormone released from adipose tissue, influences the proliferation of vascular smooth muscle cells (SMCs). Addition of adiponectin to quiescent porcine coronary artery SMCs increased both protein and DNA synthesis and concurrently activated ERK1/2 and Akt. By contrast, globular adiponectin, a truncated form of this protein, exhibited anti-mitogenic properties as indicated by the inhibition of protein and DNA synthesis in SMCs stimulated with platelet-derived growth factor (PDGF). Whereas globular adiponectin did not stimulate growth-related signal transduction pathways, it was able to block the PDGF-dependent phosphorylation of eukaryotic elongation factor 2 kinase, a regulator of protein synthesis. Proteolysis of adiponectin with trypsin, which produces globular adiponectin, reversed the growth-stimulating actions of the undigested protein. As the existence of globular adiponectin remains controversial, western blotting was used to establish its presence in rat serum. We found that globular adiponectin was detectable in rat serum, but this result was not obtained with all antibodies. The contrasting properties of adiponectin and its globular form with respect to SMC proliferation suggest that protection against atherosclerosis may therefore be mediated, in part, by the level of globular adiponectin.

Conjugated linoleic acid improves blood pressure by increasing adiponectin and endothelial nitric oxide synthase activity.

Conjugated linoleic acid (CLA) has been reported to reduce blood pressure in obese insulin-resistant rats, but its mechanism of action has not been identified. The objective of this study was to determine whether CLA isomers can reduce obesity-related hypertension in the fa/fa Zucker rat in relation to adiponectin production and endothelial nitric oxide synthase (eNOS) activation. Obese fa/fa Zucker rats were randomly assigned to one of four groups: (1) cis-9,trans-11-CLA, (2) trans-10,cis-12 (t10,c12)-CLA, (3) control or (4) captopril. After 8 weeks, systolic blood pressure increased 30% in control obese rats. This increase was attenuated 11%-13% in the t10,c12-CLA isomer and captopril groups, respectively. The t10,c12-CLA isomer concurrently elevated adiponectin levels in both plasma and adipose tissue and increased phosphorylated eNOS in adipose tissue as well as the aorta. Although a direct effect of CLA was not observed in cultured endothelial cells, direct adiponectin treatment increased phosphorylation of eNOS. Endothelial nitric oxide synthase phosphorylation was also increased in adipose of fa/fa Zucker rats infused with adiponectin in parallel with improvements in blood pressure. Our results suggest that the t10,c12-CLA isomer attenuates development of obesity-related hypertension, at least in part, by stimulating adiponectin production, which subsequently activates vascular eNOS.

Tyrosine kinase-independent activation of extracellular-regulated kinase (ERK) 1/2 by the insulin-like growth factor-1 receptor.

The extracellular-regulated kinase (ERK1/2) is a key conduit for transduction of signals from growth factor receptors to the nucleus. Previous work has shown that ERK1/2 activation in response to IGF-1 may require the participation of G proteins, but the role of the receptor tyrosine kinase in this process has not been clearly resolved. This investigation of IGF-1 receptor function was therefore designed to examine the contribution of the receptor tyrosine kinase to ERK1/2 activation. Phosphorylation of ERK1/2 in smooth muscle cells following treatment with IGF-1 was not blocked by pretreatment with AG1024 or picropodophylin, inhibitors of the IGF-1 receptor tyrosine kinase. Likewise, IGF-1 activated ERK1/2 in cells expressing a kinase-dead mutant of the IGF-1 receptor. ERK1/2 activation was unaffected by the phosphatidylinositol 3-kinase inhibitor LY-294002, but was sensitive to inhibitors of Src kinase, phospholipase C and Gßγ subunit signalling. Treatment with αIR-3, a neutralizing monoclonal antibody, also stimulated ERK1/2 phosphorylation without concomitant activation of the receptor tyrosine kinase. Phosphoprotein mapping of IGF-1 and αIR-3 treated cells confirmed that antibody-induced ERK1/2 phosphorylation occurred in the absence of tyrosine kinase phosphorylation, and enabled extension of these findings to p38 MAPK. These results suggest that stimulation of ERK1/2 phosphorylation by IGF-1 does not require activation of the receptor tyrosine kinase.

Biological response of hepatomas to an extract of Fagopyrum esculentum M. (buckwheat) is not mediated by inositols or rutin.

Buckwheat contains d-chiro-inositol (D-CI) and myo-inositol (MI), possible insulin-mimetic compounds; thus, this study investigated the insulin-mimetic activities of a buckwheat concentrate (BWC), D-CI, and MI on insulin signal transduction pathways and glucose uptake with H4IIE rat hepatoma cells. BWC stimulated phosphorylation of p42/44 extracellular-related kinase (p42/44 ERK) and its downstream target, p70(S6K), on Thr(421). In contrast, D-CI, MI, rutin, or its agylcone form, quercetin, did not activate these signal transduction proteins. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), another target of insulin, was also up-regulated upon BWC treatment. The effects of BWC on glucose uptake were subsequently investigated using H4IIE cells. Insulin and D-CI stimulated glucose uptake, whereas BWC inhibited basal and insulin-stimulated glucose uptake. Although results from this work suggest that BWC has insulin-mimetic effects on select protein phosphorylation events in H4IIE cells, D-CI and MI were not the active components responsible for the observed effects. The inhibition of glucose uptake by BWC suggests that buckwheat may affect hepatic glucose metabolism, possibly by inhibiting glucose flux. Furthermore, the fact that D-CI and MI stimulated glucose uptake in H4IIE cells suggests that other compounds are responsible for inhibition of glucose uptake by BWC.

IGF-1 receptor transactivation mediates Src-dependent cortactin phosphorylation in response to angiotensin II.

Release of angiotensin II (Ang II) after vascular injury promotes tissue repair by stimulating phenotypic modulation of smooth muscle cells, which enables cell proliferation and migration. This process requires cytoskeleton remodeling, which involves cortactin, a scaffold protein that is phosphorylated by Src kinase in response to Ang II. Since insulin-like growth factor (IGF)-1 receptor transactivation mediates intracellular signals originating from the Ang II type 1 (AT1) receptor in a Src kinase-dependent manner, we examined whether IGF-1 receptor transactivation was also required for cortactin phosphorylation. Treatment of quiescent smooth muscle cells with Ang II resulted in both cortactin phosphorylation and its translocation to the plasma membrane. Both events were prevented by 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine (PP1), a Src kinase inhibitor, and by AG1024, an inhibitor of the IGF-1 receptor tyrosine kinase. Additionally, PP1 and AG1024 blocked the association of cortactin with actin-related protein (Arp) 3, an actin nucleation factor. These results indicate that Src kinase and the IGF-1 receptor kinase are necessary for activating cortactin. Phosphorylation of Src kinase in Ang II-treated cells was subsequently examined and was shown to be prevented by AG1024. Furthermore, Src kinase phosphorylation was blocked by inhibitors of protein kinase C (PKC), but not by inhibitors of phosphatidylinositol (PI) 3-kinase. These data establish that IGF-1 receptor transactivation is required for Src kinase-mediated cortactin phosphorylation and cytoskeletal reorganization in response to Ang II.

Seasonal variation and bioactivity in the leaf oil of Liriodendron tulipifera growing in Huntsville, Alabama.

The seasonal variation in the chemical composition of the leaf essential oil of Liriodendron tulipifera has been analyzed by GC-MS. Two individual trees were sampled five times during the course of the growing season. Twenty components were identified in the leaf oils, which were dominated by sesquiterpene hydrocarbons, principally germacrene D and beta-elemene, in the early part of the season (42-44% and 18-23%, respectively,) but monoterpene hydrocarbons, largely (Z)-beta-ocimene, dominated the later season leaf oils (40-60%). The leaf oils exhibited in-vitro antibacterial activity against Bacillus cereus and Staphylococcus aureus as well as cytotoxic activity on MDA-MB-231 and Hs 578T human breast tumor cells.

Essential oil compositions and cytotoxic activities of Dendropanax capillaris, Oreopanax nubigenus, and Schefflera rodrigueziana from Monteverde, Costa Rica.

The leaf essential oils of Dendropanax capillaris, Oreopanax nubigenus and Schefflera rodrigueziana (Araliaceae) were isolated by hydrodistillation and analyzed by GC-MS. The leaf oil of Dendropanax capillaris was composed of only four compounds, beta-pinene (25.3%), 6-3-carene (44.7%), daucene (17.1%), and dauca-5,8-diene (12.9%). Oreopanax nubigenus leaf oil was dominated by the sesquiterpene hydrocarbons germacrene D (70.1%) and beta-caryophyllene (11.8%), while Schefflera rodrigueziana leaf oil was made up entirely of sesquiterpene hydrocarbons, mostly germacrene D (27.6%), beta-cubebene (27.2%), beta-caryophyllene (12.2%), beta-cubebene (11.1%), and alpha-copaene (10.8%). Both O. nubigenus and S. rodrigueziana leaf oils showed notable in-vitro cytotoxicity on MDA-MB-231 cells, which may be attributable to the relatively high concentrations of germacrene D and beta-caryophyllene in those oils.

Psychiatric morbidity in male remanded and sentenced committals to Irish prisons.

OBJECTIVES: To describe the prevalence of psychiatric morbidity and the treatment needs of new committals to Irish prisons. METHODS: A population survey of 615 prisoners representing 7.9% of male committals to Irish prisons in the year of survey, 313 remands (9.6% of total remand committals) and 302 sentenced committals (6.4% of total sentenced committals). The main outcome measures were ICD-10 diagnoses of mental disorder based on interviews using SADS-L and prison medical records. RESULTS: Current prevalence rates of any psychotic illness were 3.8% (remand) and 0.3% (sentenced), six month prevalence rate 5.1% (remand) and 2.6% (sentenced) and lifetime rate 9.3% (remand) and 6.6% (sentenced). Schizophrenia and drug/organic psychoses were the most common psychoses. Major depressive disorder had a current prevalence of 4.5% (remand) and 4.6% (sentenced), a six month prevalence of 4.8% (remand) and 6.0% (sentenced), and a lifetime prevalence of 8.6% (remand) and 15.9% (sentenced). Sixty-point-six per cent of the sample had a current substance misuse problem. CONCLUSIONS: There is significant psychiatric morbidity in committal prisoners.

Injury-induced expression of cytokeratins 8 and 18 by vascular smooth muscle cells requires concurrent activation of cytoskeletal and growth factor receptors.

Cytokeratins are not present in the vascular smooth muscle cells (VSMCs) of normal arteries, but they are detectable in the VSMCs of atherosclerotic lesions. A correlation between cytokeratin expression and VSMC phenotype is proposed, but an examination of VSMCs after mechanical injury has yet to be performed. Immunohistochemistry was used to monitor proteins in arterial sections. Western blotting enabled quantification of protein levels. Angioplasty of porcine femoral artery in vivo and porcine coronary artery in vitro served as models of vascular injury. Cytokeratins 8 and 18 were expressed by VSMCs in porcine femoral artery lesions 14 days after balloon angioplasty. Cytokeratins were also present in the neointima of porcine coronary artery segments placed into organ culture for 4 days. Cytokeratin expression was decreased in the presence of inhibitors that affect MAP kinase, PI3 kinase, Src kinase, and G protein, but not in the presence of an AT1 receptor antagonist. Cytokeratin expression also occurred when VSMCs were plated onto collagen in the presence of serum. We conclude that mechanical injury induces expression of cytokeratin 8 and 18 both in vitro and in vivo by synthetic VSMCs that migrate into the neointima. Furthermore, cytokeratin expression requires cellular attachment to extracellular matrix proteins in conjunction with mitogenic stimulation.