The Eczema Area and Severity Index: An update of progress and challenges in its measurement of atopic dermatitis after 20 years of use.

The Eczema Area and Severity Index is an investigator-assessed instrument reporting clinical signs of atopic dermatitis. The instrument is extensively validated in both adult and paediatric populations and recommended as a core outcome measure to assess clinical signs by the Harmonising Outcome Measures for Eczema initiative in clinical trials and was recently recommended as an option to measure signs in clinical practice. Here, we review the validation of the instrument using standard assessment criteria, explore controversies and challenges to its universal applicability and highlight future electronic adaptations. We find that the instrument demonstrates adequate performance in the measurement properties recommended by the COnsensus-based Standards for the selection of health Measurement INstruments initiative for instruments reporting clinical signs, is clinically interpretable, and is suitable for all atopic dermatitis severities. Some validation gaps remain. Information reporting on its performance in diverse populations, with emphasis on deeply pigmented skin, is promising though limited. Technological adaptations are demonstrating promising initial validation results and may facilitate remote and/or automated assessments assisting clinical care and decentralized clinical trials in the future. We find no strong evidence limiting its use in trials or clinical practice although questions pertaining to the effect of investigator training remain. We recommend that the Eczema Area and Severity Index be used in all interventional atopic dermatitis trials and be considered alongside other recommended clinical practice severity instruments.

The association between atopic dermatitis and inflammatory bowel disease in adults: A cross-sectional study in a specialized atopic dermatitis clinic.

BACKGROUND: Atopic dermatitis (AD) and inflammatory bowel disease (IBD) share genetic susceptibility loci with immune regulation functions. Atopic dermatitis was associated with IBD mostly in database studies. OBJECTIVE: To assess whether AD is associated with an increased prevalence of IBD in a tertiary dermatology clinic. METHODS: A retrospective cross-sectional analysis using medical records of adults with verified AD followed up at an AD clinic, compared with age- and sex-matched (1:2) controls from the general dermatology clinic in the same hospital. RESULTS: Overall, 9/364 (2.47%) of patients with AD had verified IBD, compared with 7/725 (0.97%) of controls (p = 0.0512). In multivariable logistic regression adjusting for age, gender and smoking, the association became significant (adjusted OR = 3.89, 95% CI: 1.28-11.85). Stratified for AD severity, only moderate-to-severe AD was associated with IBD (p = 0.035), with an adjusted OR of 4.45 (95% CI: 1.43-13.90). Mild AD was not associated with IBD, but the study was not powered for this sub-analysis. In the AD group, older age was associated with IBD (p = 0.0172). CONCLUSION: This study, in a robustly verified cohort of patients, supports an association between AD, especially the moderate-to-severe forms, and IBD. A multidisciplinary approach for patients with moderate-to-severe AD should extend to consider IBD.

Implementation of the HOME core outcome set for clinical trials of atopic eczema-barriers and opportunities: the HOME IX meeting report.

The Harmonising Outcome Measures for Eczema (HOME) initiative established a core outcome set (COS) for atopic eczema (AE) clinical trials in 2019. This set encompasses four core outcome domains and corresponding measurement instruments: clinical signs (EASI), patient-reported symptoms (POEM and NRS 11 point for worst itch over the last 24 h), quality of life (DLQI/CDLQI/IDQoLI), and long-term control (Recap or ADCT). Following its roadmap, the HOME initiative is now focused on supporting implementation of the COS. To identify barriers and facilitators to implementation of the COS, and to guide the effort to promote COS uptake, a virtual consensus meeting was held over 2 days (September 25-26, 2021) attended by 55 participants (26 healthcare professionals, 16 methodologists, 5 patients, 4 industry representatives, and 4 students). Implementation themes were identified by a pre-meeting survey distributed to HOME members, presentations, and whole-group discussion. Participants were divided into five multi-professional small groups which ranked their top 3 most important themes, followed by whole-group discussion and anonymous consensus voting (consensus criteria: < 30% disagreement). Three most important implementation themes were identified and agreed upon: (1) awareness and stakeholder engagement, (2) universal applicability of the COS, and (3) ensuring minimum administrative burden. Working groups to address these issues are now a priority for the HOME initiative. The results from this meeting will inform the development of a HOME Implementation Roadmap in an effort to support other COS groups planning for effective implementation of their core sets.

Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

Conjunctivitis in atopic dermatitis patients with and without dupilumab therapy - international eczema council survey and opinion.

BACKGROUND: Conjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab. OBJECTIVE: To survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC). METHODS: Electronic survey and in-person discussion of management strategies. RESULTS: Forty-six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new-onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist. LIMITATIONS: The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey. CONCLUSION: The IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab.

Optimization of placebo use in clinical trials with systemic treatments for atopic dermatitis: an International Eczema Council survey-based position statement.

BACKGROUND: As novel systemic therapeutics for patients with atopic dermatitis (AD) are developed, ethical and methodological concerns regarding placebo-controlled-trials (PCT) have surfaced. OBJECTIVE: To guide the design and implementation of PCT in AD, focusing on trials with systemic medications. METHODS: A subgroup of the International Eczema Council (IEC) developed a consensus e-survey, which was disseminated to IEC members. RESULTS: The response rate was 43/82 (52%). Consensus was reached on 24/27 statements and on 3/11 options from multiple-selection statements, including: performing monotherapy studies in proof-of-concept phases; avoiding concomitant topical corticosteroids or calcineurin inhibitors until a predefined timepoint as rescue (borderline consensus); selection of sites and assessors with recognized expertise in AD clinical trials; clear definition and identification of baseline disease severity; minimizing time and proportion of patients on placebo; using daily emollients with several options provided; instigating open-label extension studies for enrolment after a predefined timepoint; and including outcomes which set a higher bar for disease clearance. CONCLUSION: Conducting PCT in AD requires balancing several, sometimes opposing principles, including ethics, methodology, regulatory requirements and real-world needs. This paper can provide a framework for conducting PCT with systemic medications for patients with AD.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Psychological stress and psoriasis: a systematic review and meta-analysis.

BACKGROUND: Psychological stress has long been linked with the exacerbation/onset of psoriasis. OBJECTIVES: To determine if antecedent psychological stress is associated with the exacerbation/onset of psoriasis. METHODS: A search of the PubMed, PsycINFO, Cochrane library and ClinicalTrials.gov databases was performed. Surveys evaluating beliefs about stress reactivity were analysed separately. Suitable studies were meta-analysed. RESULTS: Thirty-nine studies (32 537 patients) were included: 19 surveys, seven cross-sectional studies, 12 case-control studies and one cohort study. Forty-six per cent of patients believed their disease was stress reactive and 54% recalled preceding stressful events. Case-control studies evaluating stressful events rates prior to the exacerbation (n = 6) or onset (n = 6) of psoriasis varied in time lag to recollection (≤ 9 months to ≥ 5 years). Pooling five studies evaluating stressful events preceding onset of psoriasis gave an odds ratio (OR) of 3·4 [95% confidence interval (CI) 1·8-6·4; I2 = 87%]; the only study evaluating a documented stress disorder diagnosis reported similar rates between patients and controls (OR 1·2, 95% CI 0·8-1·8). Four studies evaluating stressful events prior to psoriasis exacerbation reported comparable rates with controls, whereas two found more frequent/severe preceding events among patients with psoriasis. A small prospective cohort study reported a modest association between stress levels and exacerbation of psoriasis (r = 0·28, P < 0·05). CONCLUSIONS: The association between preceding stress and exacerbation/onset of psoriasis is based primarily on retrospective studies with many limitations. No convincing evidence exists that preceding stress is strongly associated with exacerbation/onset of psoriasis.

Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

What the Eczema Area and Severity Index score tells us about the severity of atopic dermatitis: an interpretability study.

BACKGROUND: The Eczema Area and Severity Index (EASI) is an investigator-assessed instrument measuring the severity of clinical signs in atopic dermatitis (AD). The EASI was identified as one of the best-validated outcome measures for AD; however, no previous studies address how to interpret the EASI score for clinical use. OBJECTIVES: To evaluate the interpretability and the ease of use of the EASI. METHODS: A retrospective analysis of paediatric and adult patients with AD was performed. Interpretability was evaluated by stratifying the EASI scores according to the Investigator's Global Assessment. The severity strata displaying the highest kappa coefficient of agreement were then selected as the recommended EASI band. The time to administer the EASI was recorded in a subgroup of patients. RESULTS: The suggested severity strata for the EASI are as follows: 0 = clear; 0·1-1·0 = almost clear; 1·1-7·0 = mild; 7·1-21·0 = moderate; 21·1-50·0 = severe; 50·1-72·0 = very severe (κ = 0·75). The EASI was also found to be acceptable in terms of ease of use, with assessments by trained investigators taking approximately 6 min. CONCLUSIONS: Our study provides the first guide for interpreting the EASI score. It enables translation of the EASI numerical output into an AD global severity state that should be more meaningful to providers and patients. Along with a short administration time, the EASI demonstrates adequate feasibility, further supporting its use in clinical trials.

A prospective study on clinical response and cell-mediated immunity of pemphigus patients treated with rituximab.

Rituximab has recently been reported in retrospective studies to be effective in pemphigus at the dosing schedule used for treating rheumatoid arthritis (RA) of two 1,000 mg infusions 2 weeks apart. While the effect of rituximab on B cells has been well described, its effect on global T cell function has not been assessed. Ten patients who received RA dosage rituximab were prospectively assessed for clinical response. Immunological response including autoantibody titers, CD20+ B cell, and CD4+ T cell counts was assessed pre- and post-treatment. The CD4+ T cell function was determined by a novel assay measuring intracellular ATP levels in response to mitogenic stimulus. At 6 months, 90 % of patients achieved remission. Disease control and remission were achieved at median times of 1 and 3.7 months, respectively. There was a 67 % relapse rate during an average follow-up of 22 months. Global CD4+ T cell numbers and function were preserved 3 months after rituximab. A single cycle of RA dosage rituximab with concomitant immunosuppression is effective in pemphigus. We did not find an effect on total CD4+ T cell numbers or function 3 months after treatment.

Trends in pemphigus research over 15 years.

BACKGROUND: Although pemphigus is a rare autoimmune blistering disease, it attracts the attention of physicians of many disciplines. OBJECTIVE: This study aims to assess the number of articles on pemphigus that have been published over 15 years in dermatology vs. non-dermatology medical journals, and to evaluate the quality of available evidence. METHODS: PubMed was searched for articles on pemphigus published between 1 January 1993 to 31 December 2007 using the search word pemphigus. Articles were characterized by publication type and journal type per year. Regression analysis was used to determine the effect of year of publication on number of publications of each type. RESULTS: The search yielded 2032 publications on pemphigus during the evaluation period. Sixty-one per cent were published in dermatology journals. Overall, the number of publications increased linearly with time. Most of this increase was accounted for by publications in non-dermatology journals. There was an increase in clinical trials over the course of the study period. The number of certain publications with lower quality of evidence, mainly case reports and letters to the editor, increased significantly in the last few years. There was no increase in publications with high quality of evidence. CONCLUSIONS: The increase on data from non-dermatology disciplines is a welcome contribution. Nevertheless, high-quality evidence on pemphigus is still lacking. We trust that the current trend towards evidence-based dermatology will impact future research on this severe disease.

Early-age heat exposure affects skeletal muscle satellite cell proliferation and differentiation in chicks.

Exposure of young chicks to thermal conditioning (TC; i.e., 37 degrees C for 24 h) resulted in significantly improved body and muscle growth at a later age. We hypothesized that TC causes an increase in satellite cell proliferation, necessary for further muscle hypertrophy. An immediate increase was observed in satellite cell DNA synthesis in culture and in vivo in response to TC of 3-day-old chicks to levels that were significantly higher than those of control chicks. This was accompanied by a marked induction of insulin-like growth factor-I (IFG-I), but not hepatocyte growth factor in the breast muscle. No significant difference between treatments in plasma IGF-I levels was observed. A marked elevation in muscle regulatory factors on day 5, followed by a decline in cell proliferation on day 6 together with continuous high levels of IGF-I in the TC chick muscle may indicate accelerated cell differentiation. These data suggest a central role for IGF-I in the immediate stimulation of satellite cell myogenic processes in response to heat exposure.

Risk factor clustering in hypertensive patients: impact of the reports of NCEP-II and second joint task force on coronary prevention on JNC-VI guidelines.

INTRODUCTION: Although the association of hypertension with established risk factors has been noted in several population studies, the recent redefinition of dyslipidaemia, hypertension and diabetes calls for reassessment of the prevalence and pattern of risk factor clusters in essential hypertension. OBJECTIVE: To analyse the risk factor profile of Israeli patients with essential hypertension seen by primary care physicians and in hypertension specialty clinics, based on current definitions of dyslipidaemia hypertension and diabetes and JNC-VI guidelines for the assessment of risk factors. DESIGN AND SETTING: We analysed the risk profile of 324 Israeli hypertensive subjects using the JNC-VI risk table and risk grouping. A total of 122 consecutive patients were recruited from primary care clinics and 212 consecutive patients were recruited from a hospital based hypertension clinic. RESULTS: Amongst hypertensive individuals with no known target organ damage, only 1.5% had no risk factors other than hypertension, whereas all hypertensives with coronary artery disease had additional risk factors. Of the six listed major JNC-VI risk factors (smoking, dyslipidaemia, diabetes, age, sex, family history of cardiovascular disease), hypertensive subjects without coronary artery disease (coronary artery disease-negative) had 3.02 +/- 0.10 risk factors, whereas hypertensive subjects with coronary artery disease (coronary artery disease positive) had 3.6 +/- 0.07 risk factors other than hypertension (P < 0.01). Dyslipidaemia defined by NCEP-II criteria was the most common associated risk factor identified in 93% of coronary artery disease-positive and 77% of the coronary artery disease-negative hypertensive subjects. The most common dyslipidaemic abnormality was an increased LDL cholesterol (79.2% of the cohort), followed by hypertriglyceridaemia (31.7%) and low HDL cholesterol (22.3%). Nevertheless, in nearly half of the coronary artery disease-negative patients, LDL cholesterol concentrations were within 30 mg dL-1 of the target levels. The most common dyslipidaemic variant was isolated hypercholesterolaemia (42%), whereas the syndrome X dyslipidaemic combination of hypertriglyceridaemia and low HDL was strikingly uncommon, observed in 2.8% of the coronary artery disease-positive and 0.8% of the coronary artery disease-negative patients. CONCLUSIONS: (i) JNC-VI group risk A patients (no risk factors) comprise a very small minority in this cohort (< 5%); (ii) dyslipidaemia is exceedingly common with mild hypercholesterolaemia being the most prevalent variant and hypertriglyceridaemia with low HDL the least common form.

Non-invasive photoacoustic spectroscopic determination of relative endogenous nitric oxide and ethylene content stoichiometry during the ripening of strawberries Fragaria anannasa (Duch.) and avocados Persea americana (Mill.).

Employing non-invasive photoacoustic spectrometry, emissions of nitric oxide (NO) and ethylene in post-harvest strawberries and avocados were monitored. A clear-cut stoichiometric relationship was found between the two gases: unripe fruit manifesting high NO and low ethylene levels-the converse in ripe fruit. Findings are discussed in the light of putative control of ethylene-promoted fruit senescence by endogenous NO.

Hepatocyte growth factor (HGF) inhibits skeletal muscle cell differentiation: a role for the bHLH protein twist and the cdk inhibitor p27.

Hepatocyte growth factor (HGF) plays a crucial role in regulating the differentiation of both fetal and adult skeletal myoblasts. This study aimed at defining the intracellular factors that mediate the effect of HGF on adult myoblast differentiation. HGF increased Twist expression while decreasing p27(kip1) protein levels and not affecting the induction of p21(Cip1/Waf1) in satellite cells. Like HGF, overexpression of Twist did not affect p21 expression while inhibiting muscle-specific proteins. Both ectopic Twist-antisense (Twist-AS) and p27 partially rescued the effects of HGF on bromodeoxyuridine (BrdU) incorporation and myosin heavy chain (MHC) expression in muscle satellite cells; the two plasmids together effected full rescue, suggesting that HGF independently regulates these two factors to mediate its effects. Ectopic p27 promoted differentiation in the presence of HGF by blocking the induction of Twist. Using Twist-AS to lower Twist levels restored the HGF-dependent reduction of p27 and MHC. In the presence of ectopic HGF, satellite cells formed thin mononuclear myotubes. Neither ectopic p27, Twist-AS, or their combination reversed this change in cell morphology, suggesting that HGF acts through additional mediators to inhibit downstream events during myogenesis. Taken together, the results suggest that the effects of HGF on muscle cell proliferation and differentiation are mediated through changes in the expression levels of the myogenic-inhibitory basic helix-loop-helix (bHLH) protein Twist and the cell-cycle inhibitor p27.

[Multicenter community-based trial of amlodipine in hypertension in Israel].

The safety and efficacy of Amlodipine (AML) for mild to moderate hypertension was evaluated in a "real life" setting. This open non-comparative trial included 123 men and 143 women (age 30-91 years, mean 59.4). All had sitting diastolic blood pressure (DBP) between 95 and 115 mmHg, confirmed in most by 2 baseline measurements, 2 weeks apart. Eligible patients were given AML 5 mg daily as add-on or monotherapy and were evaluated 4 weeks later. If DBP was then > 90 mmHg, the daily dose was raised to 10 mg; those with < 90 mmHg remained on 5 mg. AML was continued for 8 weeks. Other BP-lowering drugs were unchanged. Of the original 266 patients 22 (8.2%) withdrew due to adverse events (AE), and others were protocol violators, lost to follow-up or withdrew, leaving 211 available for efficacy analysis. In this major group BP was reduced from 165 +/- 15/101 +/- 4 to 139 +/- 11/83 +/- 5 after 12 weeks of AML (p < 0.05). The reduction was greater in those under 70 years, from 173 +/- 12/100 +/- 5 to 142 +/- 12/80 +/- 4 (p < 0.05). In those with BMI > 30 kg/m2, BP decreased from 165 +/- 15/101 +/- 5 to 140 +/- 12/83 +/- 5 (p < 0.05). Mean change in heart rate was -1.5 bpm (p < 0.05). Mean final AML dose was 5.5 mg/day. The most common AML-related AE requiring cessation of the drug was pedal edema in 2.6% of the 266 patients; in 3.7% it persisted during therapy. Other AE occurring in > 1% were dizziness in 1.8%, headache 1.5%, flushing 1.1% and fatigue 1.1%. We conclude that AML is an effective and well-tolerated antihypertensive suitable for most hypertensive patients.

Do Selye's mammalian "GAS" concept and "co-stress" response exist in plants?

Converging data indicate the possible existence of a general adaptation syndrome (GAS) in which different types of stress evoke identical coping mechanisms. In Selyean terms, this implies a "co-stress" response whereby one type of stress resistance may impart co-resistance to others. Common coping denominators may be physiological or morphological. The former include oxy-free radical scavenging, osmoregulation, ABA, jasmonates, chaperones, HSPs, and phytochelatins. Morphological GAS adaptations include leaf pubescence, movements and stance, and rooting characteristics. The feasibility, with certain reservations, of the GAS hypothesis is discussed here.

Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation.

The role of hepatocyte growth factor (HGF) and its receptor, c-met, in proliferation and differentiation of satellite cells was studied in primary cultures of chicken skeletal muscle satellite cells and a myogenic C2 cell line. HGF mRNA was expressed mainly in the myotubes of both cultures. The addition of conditioned medium derived from those cultures had a scattering effect on the canine kidney epithelial cell line, MDCK. In contrast, c-met mRNA levels decreased during cell differentiation of C2 and primary satellite cells. Application of exogenous HGF to chicken myoblasts resulted in their enhanced DNA synthesis. Among several growth factors, HGF was the first to induce DNA synthesis in quiescent satellite cells, thereby driving them into the cell cycle. Ectopic expression of chicken HGF in primary satellite cells suppressed the activation of muscle-regulatory gene reporter constructs MCK-CAT, MRF4-CAT, MEF2-CAT and 4Rtk-CAT, as well as the gene expression of MyoD and myogenin, and MHC protein expression. Ectopic MyoD reversed HGF's inhibitory effect on MCK transactivation. These data suggest that HGF inhibits cell differentiation by inhibiting the activity of basic helix-loop-helix (bHLH)/E protein heterodimers, thus inhibiting myogenic determination factor activity and subsequent muscle-specific protein expression. During muscle growth and regeneration, HGF plays a dual role in satellite-cell myogenesis, affecting both the proliferation and differentiation of these cells in a paracrine fashion.