Effectiveness of the Walking in ScHools (WISH) Study, a peer-led walking intervention for adolescent girls: results of a cluster randomised controlled trial.

BACKGROUND: Most adolescent girls fail to meet current physical activity guidelines. Physical activity behaviours track from childhood into adulthood and providing adolescent girls with opportunities to be physically active may have health benefits beyond childhood. The effects of walking interventions on adult cardiometabolic health are known, however less is understood about the potential of walking to promote physical activity in adolescents. Following the Walking In ScHools (WISH) feasibility study, this definitive trial aimed to evaluate the effectiveness of a novel, low-cost, school-based walking intervention at increasing physical activity levels of adolescent girls (aged 12-14 years). METHODS: Female pupils were recruited from eighteen schools across the border region of Ireland and in Northern Ireland. In intervention schools (n = 9), girls aged 15-18 years, were trained as walk leaders, and led the younger pupils in 10-15 min walks before school, at break and lunch recess. All walks took place in school grounds and pupils were encouraged to participate in as many walks as possible each week. The primary outcome measure was accelerometer determined total physical activity (counts per minutes, cpm). RESULTS: In total, 589 pupils were recruited to the study. At baseline, pupils engaged in a median (interquartile range (IQR)) 35.7 (21.2) mins moderate-vigorous physical activity (MVPA) per day and only 12% (n = 66) of participants met physical activity guidelines (60 min MVPA per day). The intervention was delivered for a mean (standard deviation (SD)) 19.9 ± 0.97 weeks. The mean post-intervention total physical activity for the intervention group was 676 cpm and 710 cpm in the control group. Post-intervention total physical activity did not statistically differ between groups when adjusted for age, body mass index z-scores and baseline physical activity (mean difference, -33.5, 95% CI = -21.2 to 88.1; p = 0.213). CONCLUSIONS: 'Scaling-up' physical activity interventions is challenging and despite a promising feasibility study, the results of this fully powered trial suggest that in this context, the WISH intervention did not increase device measured physical activity. Since the COVID-19 pandemic, school environments have changed and although pupils enjoyed the programme, attendance at walks was low, indicating that there is a need to better understand how to implement interventions within schools. TRIAL REGISTRATION: ISRCTN; ISRCTN12847782; Registered 2nd July 2019.

A peer-led walking intervention for adolescent girls (the WISH study): a cluster-randomised controlled trial.

BACKGROUND: Adolescent girls in the UK and Ireland fail to meet physical activity (PA) guidelines. PA behaviours track from childhood into adulthood. The effects of walking interventions on adult health are known; however, the potential of walking to promote PA in adolescents is less known. This study evaluated the effectiveness of a novel, school-based walking intervention aimed at increasing PA levels of adolescent girls. METHODS: In this cluster-randomised controlled trial, female pupils aged 12-14 years were recruited from 18 (mixed or single-sex) schools across the border region of Ireland and Northern Ireland. Schools were randomly assigned to either the control group (usual physical activity; n=9) or the intervention group (n=9) by independent faculty staff using an online randomisation tool (randomization.com). In intervention schools, female pupils aged 15-18 years were trained as walk leaders and led the younger pupils in 10-15 min walks before school, at break, and at lunchtime. Walks were in school grounds and pupils were encouraged to join as many walks as possible. The intervention was delivered for a full school year excluding holidays (for a total of 18-21 weeks). Accelerometers measured PA, and the primary outcome was total PA (counts per minute [cpm]). Ethics approval was granted by Ulster University Research Ethics Committee and written informed consent (parent or guardian) and assent (pupils) was obtained. This study is registered with the ISRCTN Registry, 12847782. FINDINGS: The study took place from Sept 1, 2021, to May 31, 2023. In total, 589 pupils were recruited (n=286 in intervention group; n=303 in control group). Median moderate-vigorous PA (MVPA) at baseline was 36·1 min/day (IQR 23·0) for the intervention group and 35·3 min/day (19·8) for the control group. Only 37 (15%) girls in the intervention group and 29 (10%) girls in the control group met PA guidelines (60 min/day of MVPA). The mean total PA after intervention was 676 cpm (SD 18·7) for the intervention group and 710 cpm (SD 17·7) for the control group. Post-intervention total PA did not differ between groups when adjusted for age, body-mass index, z-scores, and baseline PA (mean difference -33·5, 95% CI -21·2 to 88·1; p=0·213). INTERPRETATION: Scaling up PA interventions is challenging. Despite a promising feasibility study, the results of this fully powered trial indicate that in this context, the walking programme did not increase PA. Since the COVID-19 pandemic, school environments have changed, and although pupils enjoyed the programme, attendance at walks was low. There is a need to better understand the implementation of interventions such as this within schools. FUNDING: Cross-border Healthcare Intervention Trials in Ireland Network (CHITIN).

Changes in Physical Activity, Sleep, Mental Health, and Social Media Use During COVID-19 Lockdown Among Adolescent Girls: A Mixed-Methods Study.

BACKGROUND: To suppress the transmission of coronavirus, many governments, including that of the island of Ireland, implemented a societal lockdown, which included school closures, limits on social gatherings, and time outdoors. This study aimed to evaluate changes in physical activity (PA), mental health, sleep, and social media use among adolescent girls during lockdown. METHODS: 281 female pupils (12-14 y) taking part in the ongoing Walking In Schools study on the island of Ireland self-reported PA, mental health, sleep, and social media use before (September-October 2019) and during lockdown (May-June 2020), via questionnaires. These were supplemented with open-ended structured interviews conducted with 16 girls during lockdown. RESULTS: During the period of lockdown and school closures, pupils tried new forms of PA and undertook PA with family, but there was no significant change in self-reported PA. There was a decline in health-related quality of life and motivation for exercise; however, self-efficacy for walking and happiness with appearance increased. There was no change in sleep quality or social media usage. CONCLUSIONS: Despite the many challenges that schools face as they reopen, there is a need to continue to prioritize PA and motivation for exercise to support health and well-being in adolescent girls.

A study protocol for a clustered randomised controlled trial to evaluate the effectiveness of a peer-led school-based walking intervention on adolescent girls' physical activity: the Walking In ScHools (WISH) study.

BACKGROUND: Adolescent girls in the UK and Ireland are failing to meet current physical activity guidelines. Physical activity behaviours track from childhood to adulthood and it is important that adolescent girls are provided with opportunities to be physically active. Walking has been a central focus for physical activity promotion in adults and may effectively increase physical activity levels among younger people. Following on from a pilot feasibility trial, the purpose of this cluster randomised controlled trial (c-RCT) is to evaluate the effectiveness of a novel, low-cost, peer-led school-based walking intervention delivered across the school year at increasing physical activity levels of adolescent girls. METHODS: The Walking In ScHools (WISH) Study is a school-based c-RCT conducted with girls aged 12-14 years from eighteen schools across the Border Region of Ireland / Northern Ireland. Following baseline data collection, schools will be randomly allocated to intervention or control group. In intervention schools, female pupils aged 15-18 years will be invited to train as walk leaders and will lead younger pupils in 10-15 min walks before school, at break and lunch recess. All walks will take place in school grounds and pupils will be encouraged to participate in as many walks as possible each week. The intervention will be delivered for the whole school year (minimum 20-22 weeks). The primary outcome measure is accelerometer-measured total physical activity (counts per minute) (end of intervention). Secondary outcomes will include time spent in sedentary behaviour, light, moderate and vigorous intensity physical activity, anthropometry measures, social media usage and sleep. A mixed-methods process evaluation will also be undertaken. DISCUSSION: The WISH Study will examine the effectiveness of a low-cost, school-based, peer-led walking intervention in increasing physical activity in adolescent girls when delivered across the school year. If the intervention increases physical activity, it would benefit adolescent girls in the defined target area with potential for wider adoption by schools across the UK and Ireland. TRIAL REGISTRATION: ISRCTN; ISRCTN12847782; Registered 2nd July 2019.

Cow Milk Consumption Increases Iodine Status in Women of Childbearing Age in a Randomized Controlled Trial.

Background: Recent evidence has highlighted the prevalence of mild-to-moderate iodine deficiency in women of childbearing age and pregnant women, with important public health ramifications due to the role of iodine, which is required for thyroid hormone production, in neurodevelopment. Cow milk contributes the greatest amount to iodine intakes in several countries. Objective: The objective of this study was to investigate the effect of increased cow milk consumption on iodine status, thyroid hormone concentrations, and selenium status. Methods: A 12-wk randomized controlled trial was conducted in 78 low-moderate milk-consuming (<250 mL/d) healthy women (aged 18-45 y). The intervention group was asked to consume 3 L semiskimmed milk/wk, whereas the control group continued their usual milk consumption (baseline median: 140 mL/d; IQR: 40-240 mL/d). At baseline and weeks 6 and 12, participants provided a spot urine sample [urinary iodine concentration (UIC), creatinine] and a fasting blood sample (thyroid hormone concentrations, serum total selenium, selenoprotein P). Results: At baseline, the median (IQR) UIC of all participants was 78.5 µg/L (39.1-126.1 µg/L). Changes in the median UIC from baseline to week 6 (35.4 compared with 0.6 µg/L; P = 0.014) and week 12 (51.6 compared with -3.8 µg/L; P = 0.045) were significantly greater in the intervention group compared with the control group. However, despite being higher within the intervention group at weeks 6 and 12, the change in the iodine:creatinine ratio from baseline was not significantly different between groups at either week 6 (P = 0.637) or week 12 (P = 0.178). There were no significant differences in thyroid hormone concentrations or selenium status between groups at any time point. Conclusions: The present study shows that the consumption of additional cow milk can significantly increase UIC in women of childbearing age. These results suggest that cow milk is a potentially important dietary source of iodine in this population group. This trial was registered at www.clinicaltrials.gov as NCT02767167.

The Effect of Processing and Seasonality on the Iodine and Selenium Concentration of Cow's Milk Produced in Northern Ireland (NI): Implications for Population Dietary Intake.

Cow's milk is the most important dietary source of iodine in the UK and Ireland, and also contributes to dietary selenium intakes. The aim of this study was to investigate the effect of season, milk fat class (whole; semi-skimmed; skimmed) and pasteurisation on iodine and selenium concentrations in Northern Ireland (NI) milk, and to estimate the contribution of this milk to consumer iodine and selenium intakes. Milk samples (unpasteurised, whole, semi-skimmed and skimmed) were collected weekly from two large NI creameries between May 2013 and April 2014 and were analysed by inductively coupled plasma-mass spectrometry (ICP-MS). Using milk consumption data from the National Diet and Nutrition Survey (NDNS) Rolling Programme, the contribution of milk (at iodine and selenium concentrations measured in the present study) to UK dietary intakes was estimated. The mean ± standard deviation (SD) iodine concentration of milk was 475.9 ± 63.5 µg/kg and the mean selenium concentration of milk was 17.8 ± 2.7 µg/kg. Season had an important determining effect on the iodine, but not the selenium, content of cow's milk, where iodine concentrations were highest in milk produced in spring compared to autumn months (534.3 ± 53.7 vs. 433.6 ± 57.8 µg/kg, respectively; p = 0.001). The measured iodine and selenium concentrations of NI milk were higher than those listed in current UK Food Composition Databases (Food Standards Agency (FSA) (2002); FSA (2015)). The dietary modelling analysis confirmed that milk makes an important contribution to iodine and selenium intakes. This contribution may be higher than previously estimated if iodine and selenium (+25.0 and +1.1 µg/day respectively) concentrations measured in the present study were replicable across the UK at the current level of milk consumption. Iodine intakes were theoretically shown to vary by season concurrent with the seasonal variation in NI milk iodine concentrations. Routine monitoring of milk iodine concentrations is required and efforts should be made to understand reasons for fluctuations in milk iodine concentrations, in order to realise the nutritional impact to consumers.

Micronutrients, iodine status and concentrations of thyroid hormones: a systematic review.

Context: The metabolism of thyroid hormones, which are essential for normal development, involves many proteins and enzymes. It requires iodine as a key component but is also influenced by several other micronutrients, including selenium, zinc, iron, and vitamin A. Objective: This systematic review was designed to investigate the effect of micronutrient status and supplementation on iodine status and thyroid hormone concentrations. Data Sources: Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, electronic databases were searched from their inception to April 2016. Study Selection: Human studies published in English and reporting data on micronutrient status and iodine status and/or thyroid hormone concentrations were included. Studies that examined the effect of micronutrient supplementation on iodine status and/or thyroid hormone concentrations were also included. Data Extraction: A predesigned and piloted data extraction form was used to compile data from individual studies. Results: A total of 57 studies were included: 20 intervention studies and 37 observational studies. Although observational evidence suggests that concentrations of selenium, zinc, and iron are positively associated with iodine status, data from randomized controlled trials fail to confirm this relationship. Conclusions: Further studies are needed to provide greater understanding of the role of micronutrient status in iodine nutrition and thyroid function to ascertain the public health implications for populations worldwide.

Iodine knowledge is positively associated with dietary iodine intake among women of childbearing age in the UK and Ireland.

Adequate I intake is important before conception and during pregnancy for optimal infant neurodevelopment. Recent studies have highlighted the prevalence of I deficiency in the UK and Ireland. It is possible that optimal I intake may be impeded by a poor knowledge of I nutrition. This study aimed to investigate I knowledge among women of childbearing age in the UK and Ireland and to determine whether a relationship exists between I knowledge and dietary I intake. Females (aged 18-45 years) were invited to complete an online questionnaire, which assessed knowledge of I and estimated dietary I intake using a FFQ. A total of 520 females of childbearing age completed the study. I knowledge was poor; only one-third (32 %) of the participants correctly identified pregnancy as the most important stage of the lifecycle for I, and 41 % of participants could not correctly identify any health problem related to I deficiency. The median daily I intake was estimated as 152 µg/d. Almost half (46 %) of the participants failed to meet dietary recommendations (140 µg/d) for I. A higher dietary I intake was positively associated with greater I knowledge (r 0·107; P=0·016). This study suggests that knowledge of I nutrition is low among women of childbearing age, and those with a greater knowledge of I nutrition had a higher dietary I intake. Initiatives to educate women of childbearing age on the importance of I nutrition should be considered as part of a larger public health strategy to address I deficiency.

Randomized phase II clinical trial of avotermin versus placebo for scar improvement.

BACKGROUND: Scarring is a major problem following skin injury. In early clinical trials, transforming growth factor ß3 (avotermin) improved scar appearance. The aim of this study was to determine whether an injection of avotermin at the time of wound closure is effective in improving scar appearance. METHODS: Study RN1001-0042, a double-blind, randomized, within-patient, placebo-controlled trial, investigated the efficacy and safety of four doses of avotermin given once. Patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were enrolled at 20 European centres. A total of 156 patients were randomized to receive one of four doses of avotermin (5, 50, 200 or 500 ng per 100 µl, at 100 µl per linear cm of wound margin), administered by intradermal injection to the groin and distal wound margins of one leg; placebo was administered to the other leg. Scar appearance was evaluated by an independent panel of lay people (lay panel), investigators and patients. The primary efficacy variable was lay panel Total Scar Score (ToScar), derived from visual analogue scale scores for groin scars between 6 weeks and 7 months. RESULTS: Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 16·49 mm; P = 0·036). CONCLUSION: Avotermin 500 ng per 100 µl per linear cm of wound margin given once is well tolerated and significantly improves scar appearance.

TGF-beta3 and cancer: a review.

With the development of growth factors and growth factor modulators as therapeutics for a range of disorders, it is prudent to consider whether modulating the growth factor profile in a tissue can influence tumour initiation or progression. As recombinant human TGF-beta3 (avotermin) is being developed for the improvement of scarring in the skin it is important to understand the role, if any, of this cytokine in tumour progression. Elevated levels of TGF-beta3 expression detected in late-stage tumours have linked this cytokine with tumourigenesis, although functional data to support a causative role are lacking. While it has proved tempting for researchers to interpret a 'correlation' as a 'cause' of disease, what has often been overlooked is the normal biological role of TGF-beta3 in processes that are often subverted in tumourigenesis. Clarifying the role of this cytokine is complicated by inappropriate extrapolation of the data relating to TGF-beta1 in tumourigenesis, despite marked differences in biology between the TGF-beta isoforms. Indeed, published studies have indicated that TGF-beta3 may actually play a protective role against tumourigenesis in a range of tissues including the skin, breast, oral and gastric mucosa. Based on currently available data it is reasonable to hypothesize that administration of acute low doses of exogenous TGF-beta3 is unlikely to influence tumour initiation or progression.

Oestrogen and progesterone receptor status of individual foci in multifocal invasive ductal breast cancer.

Widespread acceptance of breast conserving surgery for early breast cancer has led to renewed interest in multifocality, which is seen in 13-63% of breast cancers. According to current guidelines, oestrogen/progesterone receptor status is assessed on the sample obtained at initial core biopsy or the main tumour focus in multifocal breast cancer (more than one distinct tumour focus in a quadrant). We assessed receptor status of individual foci in multifocal breast cancer. Mastectomy specimens for 18 cases of multifocal breast cancer were identified. Immunohistochemical staining for oestrogen and progesterone receptors was performed on all tumour foci. On histological examination 11 patients demonstrated two independent tumour foci, three demonstrated three foci and four demonstrated four foci. Minor differences in oestrogen receptor score were seen between foci (attributed to the subjective nature of the scoring system), which did not affect the overall positive/negative classification. Sixteen patients (88%) were oestrogen receptor-positive. Progesterone receptor staining showed more variability between foci in two patients but, since the tumours were oestrogen receptor-positive this would not have affected clinical decision-making. No major differences in oestrogen receptor status between multiple tumour foci in the same quadrant were found in this pilot study.

Direct polymerase chain reaction amplification of formalin-fixed, paraffin-wax-embedded tissue after automated sequential laser microdissection and pressure catapulting.

A robust method to facilitate rapid laser microdissection and pressure catapulting (LMPC) coupled with direct polymerase chain reaction (dPCR) to eliminate the need for extraction of DNA before a PCR-based assay is described. This sequential LMPC-dPCR method is rapid and decreases the number of processing steps, reducing the chance of tissue loss and contamination.

Cyclooxygenase-2 expression predicts survival in malignant pleural mesothelioma.

The expression of cyclooxygenase 2 (COX-2) protein is increased in many tumours and may be associated with a more aggressive phenotype. We aimed to assess COX-2 expression in a large series of archival mesothelioma specimens. Archival tissue was obtained from 86 malignant pleural mesothelioma samples (histological subtype: 42 epithelial, 28 biphasic and 16 sarcomatoid). Overexpression of COX-2 was detected by immunohistochemical analysis. Positive staining was located in the cytoplasm of malignant tumour cells. Overall 51/86 (59%) tumour sections demonstrated COX-2 overexpression. The frequency varied with histological subtype with 31/42 (73%) of epithelial sections, 14/28 (50%) of biphasic sections and 6/16 (37%) of sarcomatoid sections recorded as positive. Kaplan Meier survival analysis indicated that overexpression of COX-2 was significantly related to improved prognosis (P < 0.001) and was an independent prognostic factor in multivariant analysis. Overexpression of COX-2 protein may confer a survival advantage in mesothelioma patients.

Wound remodelling and scarring.

Wound healing usually results in a scar. No therapy currently exists for removing scars, so treatments focus on making them less obvious. Research is investigating how to prevent scars forming, inspired by what happens to foetuses in the womb.

Bulging medial edge epithelial cells and palatal fusion.

The surface of the medial edge epithelium of embryonic day 12, 13 and 14 mouse palatal shelves was observed utilising Environmental Scanning Electron Microscopy (ESEM). This technique offers the advantage of visualisation of biological samples after short fixation times in their natural hydrated state. Bulging epithelial cells were observed consistently on the medial edge epithelium prior to palatal shelf fusion. Additionally, we have used ESEM to compare the morphology and surface features of palatal shelves from embryonic day 13 to 16 mouse embryos that are homozygous null (TGF-beta3 -/-), heterozygous (TGF-beta3 +/-) or homozygous normal (TGF-beta3 +/+) for transforming growth factor beta-3 (TGF-beta3). At embryonic day 15 and 16 most TGF-beta3 +/- and +/+ embryos showed total palatal fusion, whilst all TGF-beta3 null mutants had cleft palate: the middle third of the palatal shelves had adhered, leaving an anterior and posterior cleft. From embryonic day 14 to 16 abundant cells were observed bulging on the medial edge epithelial surface of palates from the TGF-beta3 +/- and +/+ embryos. However, they were never seen in the TGF-beta3 null embryos, suggesting that these surface bulges might be important in palatal fusion and that their normal differentiation is induced by TGF-beta3. The expression pattern of E-Cadherin, beta-catenin, chondroitin sulphate proteoglycan, beta-Actin and vinculin as assayed by immunocytochemistry in these cells shows specific variations that suggest their importance in palatal shelf adhesion.

Medial edge epithelial cell fate during palatal fusion.

To explain the disappearance of medial edge epithelial (MEE) cells during palatal fusion, programmed cell death, epithelial-mesenchymal transformation, and migration of these cells to the oral and nasal epithelia have been proposed. However, MEE cell death has not always been accepted as a mechanism involved in midline epithelial seam disappearance. Similarly, labeling of MEE cells with vital lipophilic markers has not led to a clear conclusion as to whether MEE cells migrate, transform into mesenchyme, or both. To clarify these controversies, we first utilized TUNEL techniques to detect apoptosis in mouse palates at the fusion stage and concomitantly analyzed the presence of macrophages by immunochemistry and confocal microscopy. Second, we in vitro infected the MEE with the replication-defective helper-free retroviral vector CXL, which carries the Escherichia coli lacZ gene, and analyzed beta-galactosidase activity in cells after fusion to follow their fate. Our results demonstrate that MEE cells die and transform into mesenchyme during palatal fusion and that dead cells are phagocytosed by macrophages. In addition, we have investigated the effects of the absence of transforming growth factor beta(3) (TGF-beta(3)) during palatal fusion. Using environmental scanning electron microscopy and TUNEL labeling we compared the MEE of the clefted TGF-beta(3) null and wild-type mice. We show that MEE cell death in TGF-beta(3) null palates is greatly reduced at the time of fusion, revealing that TGF-beta(3) has an important role as an inducer of apoptosis during palatal fusion. Likewise, the bulging cells observed on the MEE surface of wild-type mice prior to palatal shelf contact are very rare in the TGF-beta(3) null mutants. We hypothesize that these protruding cells are critical for palatal adhesion, being morphological evidence of increased cell motility/migration.

Pathogenesis of cleft palate in TGF-beta3 knockout mice.

We previously reported that mutation of the transforming growth factor-beta3 (TGF-beta3) gene caused cleft palate in homozygous null (-/-) mice. TGF-beta3 is normally expressed in the medial edge epithelial (MEE) cells of the palatal shelf. In the present study, we investigated the mechanisms by which TGF-beta3 deletions caused cleft palate in 129 x CF-1 mice. For organ culture, palatal shelves were dissected from embryonic day 13.5 (E13.5) mouse embryos. Palatal shelves were placed singly or in pairs on Millipore filters and cultured in DMEM/F12 medium. Shelves were placed in homologous (+/+ vs +/+, -/- vs -/-, +/- vs +/-) or heterologous (+/+ vs -/-, +/- vs -/-, +/+ vs +/-) paired combinations and examined by macroscopy and histology. Pairs of -/- and -/- shelves failed to fuse over 72 hours of culture whereas pairs of +/+ (wild-type) and +/+ or +/- (heterozygote) and +/-, as well as +/+ and -/- shelves, fused within the first 48 hour period. Histological examination of the fused +/+ and +/+ shelves showed complete disappearance of the midline epithelial seam whereas -/- and +/+ shelves still had some seam remnants. In order to investigate the ability of TGF-beta family members to rescue the fusion between -/- and -/- palatal shelves in vitro, either recombinant human (rh) TGF-beta1, porcine (p) TGF-beta2, rh TGF-beta3, rh activin, or p inhibin was added to the medium in different concentrations at specific times and for various periods during the culture. In untreated organ culture -/- palate pairs completely failed to fuse, treatment with TGF-beta3 induced complete palatal fusion, TGF-beta1 or TGF-beta2 near normal fusion, but activin and inhibin had no effect. We investigated ultrastructural features of the surface of the MEE cells using SEM to compare TGF-beta3-null embryos (E 12. 5-E 16.5) with +/+ and +/- embryos in vivo and in vitro. Up to E13.5 and after E15.5, structures resembling short rods were observed in both +/+ and -/- embryos. Just before fusion, at E14.5, a lot of filopodia-like structures appeared on the surface of the MEE cells in +/+ embryos, however, none were observed in -/- embryos, either in vivo or in vitro. With TEM these filopodia are coated with material resembling proteoglycan. Interestingly, addition of TGF-beta3 to the culture medium which caused fusion between the -/- palatal shelves also induced the appearance of these filopodia on their MEE surfaces. TGF-beta1 and TGF-beta2 also induced filopodia on the -/- MEE but to a lesser extent than TGF-beta3 and additionally induced lamellipodia on their cell surfaces. These results suggest that TGF-beta3 may regulate palatal fusion by inducing filopodia on the outer cell membrane of the palatal medial edge epithelia prior to shelf contact. Exogenous recombinant TGF-beta3 can rescue fusion in -/- palatal shelves by inducing such filopodia, illustrating that the effects of TGF-beta3 are transduced by cell surface receptors which raises interesting potential therapeutic strategies to prevent and treat embryonic cleft palate.

Transforming growth factor beta s and wound healing.

The Transforming Growth Factor beta superfamily (TGF beta) is one of the most complex groups of cytokines with widespread effects on many aspects of growth and development. The TGF beta isoforms and other family members, e.g. Activins and BMPs, have diverse effects in similar physiological situations. TGF beta is involved in the wound healing process. The three mammalian isoforms (TGF beta 1, 2 and 3) and recently other family members, e.g. Activin, have been localised in healing wounds. Manipulation of the ratios of TGF beta superfamily members, particularly the ratio of TGF beta 1 relative to TGF beta 3, reduces scarring and fibrosis. Such manipulations include reducing the levels of TGF beta 1/TGF beta 2 using neutralising antibodies or preventing the activation of TGF beta s. In chronic or impaired wounds the exogenous addition of TGF beta superfamily members accelerates aspects of the healing process. This review summarises evidence for the role of TGF beta superfamily members in wound healing and how modulation of TGF beta levels can prevent scarring and fibrosis.