Assessing physical activity in people with mental illness: 23-country reliability and validity of the simple physical activity questionnaire (SIMPAQ).

BACKGROUND: Physical inactivity is a key contributor to the global burden of disease and disproportionately impacts the wellbeing of people experiencing mental illness. Increases in physical activity are associated with improvements in symptoms of mental illness and reduction in cardiometabolic risk. Reliable and valid clinical tools that assess physical activity would improve evaluation of intervention studies that aim to increase physical activity and reduce sedentary behaviour in people living with mental illness. METHODS: The five-item Simple Physical Activity Questionnaire (SIMPAQ) was developed by a multidisciplinary, international working group as a clinical tool to assess physical activity and sedentary behaviour in people living with mental illness. Patients with a DSM or ICD mental illness diagnoses were recruited and completed the SIMPAQ on two occasions, one week apart. Participants wore an Actigraph accelerometer and completed brief cognitive and clinical assessments. RESULTS: Evidence of SIMPAQ validity was assessed against accelerometer-derived measures of physical activity. Data were obtained from 1010 participants. The SIMPAQ had good test-retest reliability. Correlations for moderate-vigorous physical activity was comparable to studies conducted in general population samples. Evidence of validity for the sedentary behaviour item was poor. An alternative method to calculate sedentary behaviour had stronger evidence of validity. This alternative method is recommended for use in future studies employing the SIMPAQ. CONCLUSIONS: The SIMPAQ is a brief measure of physical activity and sedentary behaviour that can be reliably and validly administered by health professionals.

BRCA1 regulation on ß-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer.

Human chorionic gonadotropin ß (ß-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of ß-hCG in breast cancer. We identified for the first time that ß-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and ß-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of ß-hCG by binding to its promoter. Further, ß-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of ß-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since ß-hCG belongs to a cysteine knot family of proteins like TGFß and TGFß signaling is deregulated in BRCA1 defective tumors, we checked whether ß-hCG can mediate signaling through TGFßRII in BRCA1 mutated cells. We found for the first time that ß-hCG can bind and phosphorylate TGFßRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on ß-hCG and BRCA1 mutation promotes ß-hCG mediated tumorigenesis through TGFßRII signaling. Thus inhibiting ß-hCG-TGFßRII could prove an effective treatment strategy for BRCA1 mutated tumors.

Astaxanthin modulates osteopontin and transforming growth factor ß1 expression levels in a rat model of nephrolithiasis: a comparison with citrate administration.

OBJECTIVES: To evaluate the effect of astaxanthin on renal angiotensin-I converting enzyme (ACE) levels, osteopontin (OPN) and transforming growth factor ß1 (TGF-ß1) expressions and the extent of crystal deposition in experimentally induced calcium oxalate kidney stone disease in a male Wistar rat model. To compare the efficacy of astaxanthin treatment with a currently used treatment strategy (citrate administration) for kidney stones. MATERIALS AND METHODS: The expression of OPN was assessed by immunohistochemistry. One step reverse transcriptase polymerase chain reaction followed by densitometry was used to assess renal OPN and TGF-ß1 levels. Renal ACE levels were quantified by an enzyme-linked immunosorbent assay method. Crystal deposition in kidney was analysed by scanning electron microscopic (SEM)-energy-dispersive X-ray (EDX). RESULTS: The renal ACE levels and the expression of OPN and TGF-ß1 were upregulated in the nephrolithiasis-induced rats. Astaxanthin treatment reduced renal ACE levels and the expression OPN and TGF-ß1. SEM-EDX analysis showed that crystal deposition was reduced in the astaxanthin-treated nephrolithiatic group. Astaxanthin treatment was more effective than citrate administration in the regulation of renal ACE levels, OPN and TGF-ß1 expressions. CONCLUSIONS: Astaxanthin administration reduced renal calcium oxalate crystal deposition possibly by modulating the renal renin-angiotensin system (RAS), which reduced the expression of OPN and TGF-ß1 levels. Astaxanthin administration was more effective than citrate treatment in reducing crystal deposition and down-regulating the expression of OPN and TGF-ß1.

Chitosan scaffold co-cultured with keratinocyte and fibroblast heals full thickness skin wounds in rabbit.

This study evaluated the modulatory effect of chitosan sponge co-cultured with keratinocyte and fibroblast on wound healing. Dermal fibroblasts and keratinocyte isolated from rabbit skin were co-cultured on chitosan sponge, to fabricate cell-loaded chitosan tissue engineered construct. Full thickness excision wounds created on the rabbit dorsum were treated with three types of graft materials ­ a noncellular chitosan graft, homologous keratinocyte fibroblast loaded chitosan, and a commercial product. Postgraft skin-wound samples were examined histomorphologically at 7th, 14th, and 28th day after staining with hematoxylin and eosin, picrosirius red and/or immunohistochemistry. Wound healing parameters considered were the extent of re-epithelialization, collagen deposition, and neoangiogenesis. The number of proliferating cells, vimentin positive cells, and alpha smooth muscle actin cells were also quantified. The histology results suggested that the grafts aided wound healing but, the cell-loaded graft induced a differential pattern of healing and had lower scarring tendency. The cell-loaded tissue construct may be useful as a therapeutic graft for treating wounds where there is a total loss of tissue and cells as in burn injury.

Flexible and microporous chitosan hydrogel/nano ZnO composite bandages for wound dressing: in vitro and in vivo evaluation.

Current wound dressings have disadvantages such as less flexibility, poor mechanical strength, lack of porosity, and a tendency for dressings to adhere onto the wound surface; in addition, a majority of the dressings did not possess antibacterial activity. Hydrogel-based wound dressings would be helpful to provide a cooling sensation and a moisture environment, as well as act as a barrier to microbes. To overcome these hassles, we have developed flexible and microporous chitosan hydrogel/nano zinc oxide composite bandages (CZBs) via the incorporation of zinc oxide nanoparticles (nZnO) into chitosan hydrogel. The prepared nanocomposite bandages were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). In addition, swelling, degradation, blood clotting, antibacterial, cytocompatibility, cell attachment on the material, and cell infiltration into the composite bandages were evaluated. The nanocomposite bandage showed enhanced swelling, blood clotting, and antibacterial activity. Cytocompatibility of the composite bandage has been analyzed in normal human dermal fibroblast cells. Cell attachment and infiltration studies showed that the cells were found attached to the nanocomposite bandages and penetrated into the interior. Furthermore, the in vivo evaluations in Sprague-Dawley rats revealed that these nanocomposite bandages enhanced the wound healing and helped for faster re-epithelialization and collagen deposition. The obtained data strongly encourage the use of these composite bandages for burn wounds, chronic wounds, and diabetic foot ulcers.

Development and validation of the Domestic Violence Questionnaire in married women aged 18-55 years.

BACKGROUND: Intimate partner violence against women is seen in all cultures. It has wide-ranging effects on the physical and psychological health of women. In the local language, available questionnaires are either too exhaustive or inadequate to assess domestic violence comprehensively. OBJECTIVE: To develop a Domestic Violence Questionnaire in Malayalam and validate it for married women aged 18-55 years in the local population. STUDY DESIGN: Descriptive study - Validation of questionnaire. MATERIALS AND METHODS: A 29-item questionnaire, to identify domestic violence over the past 1 year, was developed in the local language, by selecting items from two other questionnaires and based on expert opinion. Item reduction was done after pilot testing. Then, this 25-item questionnaire was administered to 276 married women aged 18-55 years. Reliability and validity were estimated. Factor analysis was done for item reduction. Poor-loading, wrong-loading and cross-loading items were removed from the questionnaire. Taking the subjective perception of the participants regarding themselves experiencing domestic violence as the gold standard, a Receiver Operator Characteristic curve was drawn to decide the cut-off score with optimum sensitivity and specificity. RESULTS: The final questionnaire had 20 items - 13 items for psychological and 7 items for physical violence. Internal consistency reliability was 0.92. At a cut-off score of 5, sensitivity was 89.5% and specificity 87.2%. CONCLUSIONS: The Domestic Violence Questionnaire in Malayalam has adequate psychometric properties to identify intimate partner violence against women in the local population.

Advantages of hyaluronic acid as a component of fibrin sheet for care of acute wound.

Skin injury is followed by accumulation of a fibrin based provisional matrix which normally drives the process of wound repair. Exogenous fibrin with extra cellular matrix (ECM) components can also favor the wound healing process. In a preliminary study we found that lyophilized fibrin sheet (FS) arrest bleeding from rabbit skin wound but it remained dry during the repair period and did not accelerate the healing process better than untreated control. In the current study, hyaluronic acid (HA) was incorporated into FS and the resultant HA-FS promoted water retention and improved wound healing process. Gross-morphology, histopathology and histomorphometry were employed to compare qualitative and quantitative difference of wound healing in treated group against controls. In experimental sites (HA-FS), re-epithelialization was completed by 14 days with neo-vascularization and deposition of wavy bundles of collagen in the treated sites. Rate of healing process was different in treated and untreated wounds and most striking difference was the appearance of appendages, sebaceous gland and hair follicle at some locations in HA-FS treated sites. Therefore, HA with fibrin can create an effective wound care matrix which promotes water retention and wound healing potential.

Decompressive hemicraniectomy in large putaminal hematomas: an Indian experience.

OBJECTIVE: The treatment of large putaminal hematomas is predominantly medical and the role of surgery is debated. Decompressive hemicraniectomy in large hemispheric infarctions has been reported to lower mortality and improve outcomes. Decompressive hemicraniectomy may also have a role in putaminal hematomas. METHODS: In all, 23 patients with putaminal hematoma who underwent decompressive craniectomy in the last 4 years were analyzed. Parameters investigated included clinical presentations, radiologic profile, time interval from ictus to surgery, and Glasgow outcome score at 1 month. RESULTS: There were 13 men and 10 women with ages ranging from 31 to 68 years. All of them presented with neurologic deficits. Seven patients had a Glasgow Coma Scale (GCS) score of 3 to 8, 12 had a GCS score of 9 to 12, and GCS score was above 13 in 4. Seventeen patients had known hypertension. Computed tomography scan was done in all. The hematoma was less than 3 cm in 5 cases, 3 to 5 cm in 11, and larger than 5 cm in 7; and was 30 mL or less in 3, 30 to 60 mL in 13, and more than 60 mL in 7. All patients underwent hemicraniectomy on the side of the lesion and dura was left open. At 3 months, 13 patients had a good outcome and 10 had a poor outcome (including 3 deaths). CONCLUSIONS: Decompressive hemicraniectomy can be a useful alternative surgical procedure in moderate to large putaminal hematomas.

Amphotericin B-gum arabic conjugates: synthesis, toxicity, bioavailability, and activities against Leishmania and fungi.

PURPOSE: Gum arabic, a branched polysaccharide consisting of more than 90% arabinogalactan having a molecular weight around 250,000 Da is the oldest and best known of all natural gums. The objective of the present investigation was to examine whether amphotericin B (AmB), the polyene antibiotic when conjugated to periodate oxidized gum arabic still retained its anti-fungal and anti-leishmanial activity and to evaluate its toxicity and bioavailability. METHODS: AmB conjugated to the oxidized polysaccharide through Schiff's linkages in the unreduced (imine) and reduced (amine) forms were characterized for the drug content, hemolytic potential, molecular mass, in vitro release and were examined for anti-fungal activity against Candida albicans and Cryptococcus neoformans and for anti-leishmanial activity against promastigotes of Leishmania donovani in culture. Toxicity and bioavailability were evaluated by intravenous (i.v) injections of the conjugates in mice and rabbits respectively. RESULTS: The conjugates were found to be non-hemolytic and mice withstood a dosage of 20 mg (AmB)/kg body weight of both conjugates. Histological examination of the internal organs of mice showed no lesions in kidney, brain, heart or liver. Estimation of the residual drug in the internal organs 7 days post injection showed that the spleen still retained 8.4 +/- 0.53 microg/g of tissue. AmB was found to be released from both conjugates in vitro although the release from the imine conjugate was much faster than from the amine conjugate. The concentrations inhibiting parasite growth by 50% (IC(50)) values for the imine conjugate against promastigotes of L. donovani LV9 and DD8 strains were 0.37 +/- 0.04 and 1.44 +/- 0.18 microM respectively. The IC(50) values for the amine conjugates were much higher. The minimum inhibitory concentration (MIC) against C. albicans and C. neoformans was in the range of 0.5-0.9 microg/mL for both imino and amino conjugates. The bioavailability of the conjugate in rabbits showed that the imine conjugate maintained a plasma concentration in the range of 20 to 5 microg/mL while for the amine conjugate it was in the range of 17 to 3 microg/mL over 24 h. CONCLUSIONS: The drug conjugates were stable, non-hemolytic and non-toxic to the internal organs of the animal and showed good anti-fungal and anti-leishmanial activity in vitro. In spite of the large molecular weight of the polysaccharide, AmB from the conjugates showed bioavailability after i.v injection. Since the highest concentration of AmB was found in the spleen after a single injection, these conjugates may have potential in anti-leishmanial therapy.

Biological evaluation of pliable hydroxyapatite-ethylene vinyl acetate co-polymer composites intended for cranioplasty.

Hydroxyapatite (HAP) is undoubtedly a material suitable for repairing the defective bone tissue. However, the brittleness and non-malleability of HAP limit its clinical application as a cranioplastic analogue. To improve these properties, pliable, osteoconductive composites composed of HAP and ethylene vinyl acetate co-polymer (EVA) have been developed. This study reports the biocompatibility evaluation of the newly developed composite material. Composites of two compositions, containing 40 and 50 volume percentage of HAP, were evaluated. In vitro cell culture cytotoxity studies were carried out using L929 cell line. Intracutaneous irritation studies, and intramuscular implantation studies were carried out on rabbits. Cell culture studies showed that the composite was non-cytotoxic to mouse fibroblast cell line. Intracutaneous irritation studies did not show any gross signs of tissue reaction. Histological analysis after six months of implantation in the paravertebral muscles of rabbit showed that all the implants under study were covered with a thin soft tissue capsule. On the basis of these observations, we conclude that the composite materials are biocompatible and hence are a candidate material for implantation in the cranium.

Acute disseminated encephalomyelitis following leptospirosis.

Acute disseminated encephalomyelitis is very rare following leptospirosis. Here we describe a patient who developed the condition after leptospiral infection, which responded to intravenous immunoglobulin only.

Long term tissue response to titanium coated with diamond like carbon.

Diamond like carbon (DLC) coatings were deposited on to Ti substrates by plasma enhanced chemical vapor deposition technique. Ti and DLC/Ti samples were implanted in skeletal muscle of rabbits. The samples were explanted after 1, 3, 6 and 12 months and the tissue-cell interaction was studied. Our data indicate both DLC/Ti and bare Ti to be compatible with skeletal muscle.

An analysis of apoptosis in lymphoid organs and lupus disease in murine systemic lupus erythematosus (SLE).

Apoptosis is a programmed cell death process that helps to regulate both T cell and B cell development. In this study, we have investigated the levels of apoptotic death in cells of the thymuses and spleens (white matter) of autoimmune MRL-lpr/lpr mice with progressive lymphadenopathy and SLE disease activity; we also examined the renal pathology in these animals. Fas is a cell surface receptor, which when activated initiates the sequence of events that lead to apoptosis. In MRL-lpr/lpr mice Fas is defective, so the competency for apoptosis may be reduced. In young animals of advancing age the thymuses enlarged until in 5-month-old females the average weight was three times that at 1 month, and spleen and kidney weights also increased in size disproportionately. At light microscope level apoptotic cells in tissue sections were counted using both routine eosin and haematoxylin staining (to identify them by their morphology) and in situ end-labelling of cells with DNA strand breaks; their presence was further confirmed by electron microscopy. As the mice aged, the numbers of apoptotic cells in thymic cortex, thymic medulla and spleen white pulp areas reduced significantly (P < 0.01-0.001), whereas in BALB/c normal controls they increased significantly (P < 0.05). These changes were coincident with the development of severe lupus, whose activity was assessed by measuring serum anti-ssDNA and anti-dsDNA antibody titres and urinary protein (albumin) level which were elevated significantly by 5 months of age (P < 0.001 for both ssDNA and dsDNA and P < 0.01 for urine albumin) compared with their younger counterparts. Thus, lymphoid organ enlargement, decrease in apoptotic indices, elevated serum anti-ssDNA and anti-dsDNA antibody levels, and impaired renal function coincided with the onset and severity of lupus disease in lpr mice. It seems likely that there is a causal relationship between defective deletion of autoreactive lymphoid cells, imperfect Fas-mediated apoptosis and development of murine SLE.

Protein extraction and western blotting from methacarn-fixed tissue.

Polyacrylamide gel electrophoresis (PAGE) of proteins with subsequent western blotting has become a routine technique for the analysis of proteins from both cultured cells and fresh whole tissue. We have developed a method to extract proteins from methacarn-fixed tissue which renders them suitable for SDS-PAGE and western blotting. With a panel of antibodies to specific intermediate filaments, transforming growth factor-alpha (TGF-alpha), and albumin, immunohistochemistry was performed in parallel with western blotting on sections cut from methacarn-fixed samples of normal rat liver and liver from rats treated under a regime which induces oval cell proliferation. Immunohistochemistry enabled the determination of changes in tissue distribution and abundance of the target proteins, which was mirrored by the corresponding western blot data. This technique can be especially effective when used in conjunction with immunohistochemistry. Tissue samples are easy to prepare, avoiding the precautions which need to be taken when handling fresh tissue (Abstract: J Pathol 1994; 173S: No. 41).

Oval cell differentiation into hepatocytes in the acetylaminofluorene-treated regenerating rat liver.

When hepatocyte regeneration after a two-thirds partial hepatectomy (PH) in rats is blocked by oral gavage of acetylaminofluorene, a proliferation of ductular cells ensues that results in a profusion of neoductules radiating from each portal tract. To examine the possibility that this population of newly emerging cells harbors cells capable of differentiating into hepatocytes, we have looked in these cells for expression of functional markers of hepatocyte commitment at both the RNA and protein levels. Expression of albumin and alpha-fetoprotein (alpha-FP) messenger RNA (mRNA) transcripts were sought in situ using antisense riboprobes, and the expression of a number of cytochrome P450 enzymes was examined immunohistochemically. Before any signs of differentiation the ductular cells strongly expressed cytokeratins 7, 8, 18, and 19 in the same manner as authentic bile ducts, but unlike the latter also expressed vimentin. In situ hybridization studies showed that small bile ducts close to the limiting plate, as well as the newly formed ducts, expressed albumin and alpha-fetoprotein messenger RNAs, and immunocytochemistry showed that the distribution of the respective proteins was similar. Beginning at 1 week after partial hepatectomy, areas of differentiation could be found in the new ducts, with cells resembling either columnar intestinal-type epithelia or hepatocytes. Intestinal-like cells expressed neither albumin, alpha-FP, nor cytochrome P450 enzymes, whereas ductular cells appearing like hepatocytes with the typical membranous distribution of cytokeratin 8 strongly expressed a variety of cytochrome P450 enzymes normally associated with functional hepatocytes. These observations further support the belief that reactive ductules, sprouted from small ducts, can represent an adaptive response of the liver to replenish lost hepatocytes, although some of the newborn cells appear to differentiate along intestinal lines.

The resistant hepatocyte model of carcinogenesis in the rat: the apparent independent development of oval cell proliferation and early nodules.

The early cellular changes in the Solt-Farber resistant hepatocyte model of carcinogenesis have been studied to clarify the relationship of oval cell proliferation to the development of early hepatocyte nodules. Cellular proliferation, intermediate filament profiles and the expression of specific cytochrome P450 enzymes were examined. At 24 h after partial hepatectomy (PH) many of the bile ductular cells were in S phase, but over the next few days DNA synthesis progressively decreased in the portal bile ducts and was more common in arborizing ductules (oval cells) radiating from the portal areas. These cells strongly expressed cytokeratins 8 and 19 and vimentin, and from 1 week after PH they frequently underwent differentiation either into hepatocytes, expressing cytochrome P450 enzymes, or into intestinal-type cells. Five days after PH, numerous basophilic foci were discernible, and these expanded rapidly. The ductular cells swirled around the foci, but their antigenic profile clearly indicated that these cells were not involved in the development of these early nodules. In normal hepatocytes, cytokeratin 8 immunoreactivity was distinctly membranous in location, and could only be readily detected in periportal hepatocytes. In the basophilic hepatocyte foci, overexpression of cytokeratin 8 was consistently associated with cells organizing into acini, with expression reminiscent of authentic bile ducts, possibly indicating a structure-function relationship. In conclusion, early foci and nodules in this model are derived from resistant hepatocytes and not ductular oval cells, the latter being a facultative multipotential stem cell compartment.

Cell behavior in the acetylaminofluorene-treated regenerating rat liver. Light and electron microscopic observations.

When hepatocyte regeneration is impaired, facultative stem cells and their descendants, also called oval cells, become activated and produce cell progeny that eventually differentiate. We have observed these cells in the rat liver after partial hepatectomy when the animals have been fed 2-acetylaminofluorene. Oval cells emerge from the portal areas and stain strongly with monoclonal antibodies raised against cytokeratins 8 and 19 and vimentin, the intermediate filament traditionally associated with mesenchymal cells. The majority of oval cells appeared to be part of a bile ductular reaction, manifest by their cytokeratin expression, and the bile duct injection of pigmented gelatin confirmed that these oval cells were essentially tortuous, arborizing duct-like structures (cholangioles) branched from and continuous with preexisting bile ducts. In situ hybridization studies showed that hepatocyte growth factor mRNA-expressing sinusoid lining cells were most numerous in the periportal areas during the period of ductular proliferation. At 1 week after partial hepatectomy, we observed morphological evidence of areas of in situ focal differentiation in the ductular structures, either to a columnar intestinal-type epithelia or to a hepatocyte phenotype, with abundant large mitochondria and membranous cytokeratin 8 immunoreactivity contrasting with the diffuse staining of the ductular cells. By following the fate of oval cells the authors conclude that in this model proliferated bile ductules represent the oval cell compartment capable of producing pluripotential progenitor cells.

Squamous cell carcinoma of the feline thymus with widespread apoptosis.

The present report documents a case of squamous cell carcinoma originating from the thymus of a 12-year-old short-haired male cat. The tumour had metastasised to the sternal lymphoid tissue and to the left lung. To the authors' knowledge, thymic carcinoma has not been reported in domestic animals. Furthermore, extensive apoptosis was observed in the tumour mass.

Expression of hepatocyte growth factor mRNA during oval cell activation in the rat liver.

The customary wave of hepatocyte regeneration which occurs in the rat liver after two-thirds partial hepatectomy can be abolished by oral administration of the carcinogen 2-acetylaminofluorene. Instead, regeneration is achieved through the proliferation and differentiation of potential stem cells (oval cells) which appear to emanate from the portal space. Ultrastructural studies have illustrated the undifferentiated nature of these cells in the first 3 days after resection, but very rapidly they acquire features of small hepatocytes or biliary epithelia. Oval cell progeny can form either cohesive columns of cells within sinusoids which may later differentiate into new hepatic plates, or single cells that can insinuate within existing plates. Using a 35S antisense riboprobe to hepatocyte growth factor (HGF) mRNA, the synthesis of HGF mRNA was observed in sinusoid-lining cells. There were few HGF mRNA-expressing cells in the liver removed at resection, but numbers steadily increased in the remnant over the next 7 days. In particular, an almost nine-fold increase in the density of HGF mRNA-producing cells occurred in the periportal areas, resulting in approximately double the density present within the centrilobular parenchyma. The superabundance of HGF-producing cells in the immediate vicinity of oval cell proliferation and differentiation strongly suggests that this growth factor is involved in all aspects of stem cell behaviour--proliferation, migration, and differentiation, through a paracrine mechanism.