Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation.

OBJECTIVE: 3-M syndrome is characterized by severe short stature, syndromic features, and characteristic radiographic findings. Growth hormone (GH) has been used with variable success. Recombinant human insulin like growth factor-1 (rhIGF-1) has never been utilized. CASE PRESENTATION: We describe a child with severe growth retardation, macrocephaly, and skeletal abnormalities with evidence of GH insensitivity subsequently treated with rhIGF-1. He developed morbid obesity and comorbidities including voracious appetite, acanthosis nigricans, tonsillar hypertrophy, and severe obstructive sleep apnea with minimal height improvement. Genetic testing done at 11.5 years revealed a compound heterozygous mutation (c.2112G>A(p.W704X) and c.2559delC) in the CUL7 gene consistent with 3-M syndrome-1. rhIGF-1 therapy was discontinued. CONCLUSIONS: This case highlights the novel use of rhIGF-1 therapy on a child with 3-M syndrome-1 with minimal height benefit but accelerated weight gain and serves as a reminder of the importance of re-evaluating therapy efficacy and side effect profile.

Recombinant human insulin-like growth factor-1 therapy for 6 months improves growth but not motor function in boys with Duchenne muscular dystrophy.

INTRODUCTION: Recombinant human insulin-like growth factor-1 (rhIGF-1) is a growth factor and has anabolic effects on muscle. We investigated whether rhIGF-1 therapy: 1) improves or preserves muscle function; and 2) improves growth in boys with Duchenne muscular dystrophy (DMD). METHODS: In this study we compared prepubescent, ambulatory, glucocorticoid-treated boys with DMD (n = 17) vs controls (glucocorticoid therapy only, n = 21) in a 6-month-long, prospective, randomized, controlled trial of subcutaneous rhIGF-1 therapy. The primary outcome was 6-minute walk distance (6MWD). Secondary outcomes included height velocity (HV), change in height standard deviation score (ΔHtSDS), motor function, cardiopulmonary function, body composition, insulin sensitivity, quality of life, and safety. RESULTS: Change in 6MWD was similar between groups (rhIGF-1 vs controls [mean ± SD]: 3.4 ± 32.4 vs -5.1 ± 50.2 meters, P = .53). Treated subjects grew more than controls (HV: 6.5 ± 1.7 vs 3.3 ± 1.3 cm/year, P < .0001; 6-month ΔHtSDS: 0.25, P < .0001). Lean mass and insulin sensitivity increased in treated subjects. DISCUSSION: In boys with DMD, 6 months of rhIGF-1 therapy did not change motor function, but it improved linear growth.

[Advances in the research of delivery system of growth factor and the gene for promoting wound healing].

Growth factors play critical roles in the process of wound healing. Application of growth factor locally is a good way of promoting wound healing, while it is easy to be hydrolyzed in wounds and its efficacy has dose- and time-dependent manner. Therefore, appropriate growth factor delivery system is needed to assist it to function in wounds. In addition to delivering growth factor directly to wounds, viral and non-viral vectors can be used for gene transfection of growth factor in wounds. The gene can be transformed to growth factor to promote wound healing by transcription and translation. This article reviews the advances in the research of delivery system of growth factor and the gene for promoting wound healing.

Defining Hand Stereotypies in Rett Syndrome: A Movement Disorders Perspective.

INTRODUCTION: Hand stereotypies (HS) are a primary diagnostic criterion for Rett syndrome (RTT) but are difficult to characterize and quantify systematically. METHODS: We collected video on 27 girls (2-12 years of age) with classic RTT who participated in a mecasermin trial. The present study focused exclusively on video analyses, by reviewing two five-minute windows per subject to identify the two most common HS. Three raters with expertise in movement disorders independently rated the five-minute windows using standardized terminology to determine the level of agreement. We iteratively refined the protocol in three stages to improve descriptive accuracy, categorizing HS as "central" or "peripheral," "simple" or "complex," scoring each hand separately. Inter-rater agreement was analyzed using Kappa statistics. RESULTS: In the initial protocol evaluating HS by video, inter-rater agreement was 20.7%. In the final protocol, inter-rater agreement for the two most frequent HS was higher than the initial protocol at 50%. CONCLUSION: Phenotypic variability makes standardized evaluation of HS in RTT a challenge; we achieved only 50% level of agreement and only for the most frequent HS. Therefore, objective measures are needed to evaluate HS.

Heterotopic ossification related to the use of recombinant human BMP-2 in osteonecrosis of femoral head.

Despite the wide use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in bone defect, its application in treating osteonecrosis of femoral head (ONFH) is yet to be elucidated. The heterotopic ossification (HO) after rhBMP-2 usage in some orthopedic surgeries has been reported previously; however, only a few studies describe this complication in the treatment of ONFH.The present study investigated whether the rhBMP-2 application would increase the risk of HO formation in selected ONFH patients with nonvascularized bone grafting surgery and enhance the surgical results of nonvascularized bone grafting as compared to patients who did not receive intraoperative rhBMP-2.A retrospective analysis was performed on 94 patients (141 hips) who, with Association Research Circulation Osseous (ARCO) stages IIb, IIc, and IIIa ONFH, underwent nonvascularized bone grafting surgery. The first 46 patients (66 hips) received intraoperative rhBMP-2. The postoperative radiographic results (X-ray and CT scan) and Harris hip score (HHS) were reviewed in each patient to record the incidence of HO formation and evaluate the clinical efficacy of rhBMP-2, respectively.HO formation frequently occurred in patients receiving intraoperative rhBMP-2 (8/66 hips) than those not receiving the protein (1/75 hips) (P = .02). HHS improved from preoperatively at the final follow-up (P < .01) in the BMP-positive group, with a survival rate of 83.3%. In the BMP-negative group, the HHS improved from preoperatively at the end of the follow-up (P < .01), and the survival rate was 72.0%.rhBMP-2 has osteoinductive property and might serve as an adjuvant therapy in the surgical treatment of ONFH. However, the incidence of HO formation might increase when used in high doses.

Bioactive Molecule Delivery Systems for Dentin-pulp Tissue Engineering.

INTRODUCTION: Regenerative endodontic procedures use bioactive molecules (BMs), which are active signaling molecules that initiate and maintain cell responses and interactions. When applied in a bolus form, they may undergo rapid diffusion and denaturation resulting in failure to induce the desired effects on target cells. METHODS: The controlled release of BMs from a biomaterial carrier is expected to enhance and accelerate functional tissue engineering during regenerative endodontic procedures. This narrative review presents a comprehensive review of different polymeric BM release strategies with relevance to dentin-pulp engineering. RESULTS: Carrier systems designed to allow the preprogrammed release of BMs in a spatial- and temporal-controlled manner would aid in mimicking the natural wound healing process while overcoming some of the challenges faced in clinical translation of regenerative endodontic procedures. CONCLUSIONS: Spatial- and temporal-controlled BM release systems have become an exciting option in dentin-pulp tissue engineering; nonetheless, further validation of this concept and knowledge is required for their potential clinical translation.

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From in vivo Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway.

Hexarelin, a synthetic growth hormone-releasing peptide, has been proven to possess cardioprotective actions through its binding to the growth hormone secretagogue receptor (GHSR) 1a and the non-GHSR receptor CD36. However, its effect on myocardial ischemia/reperfusion (I/R) injury has not been fully clarified in vivo. We aimed to determine whether hexarelin treatment could protect cardiomyocytes from I/R injury and to examine the underlying mechanisms. In vivo hearts of male SD rats underwent 30 minutes of ischemia by left coronary artery ligation followed by reperfusion. The rats were then treated subcutaneously twice daily with hexarelin [100 µg/kg·day], ghrelin [400 µg/ kg·day], or saline for 7 days. Echocardiography, malondialdehyde detection, and histochemical staining were performed after treatment. In addition, Western blot was used to examine the expression levels of IL-1ß, IL-1Ra, and IL-1RI. Our study showed that hexarelin treatment improved cardiac systolic function, decreased malondialdehyde production, and increased the number of surviving cardiomyocytes. The beneficial effects of hexarelin treatment were slightly superior to those of equimolar ghrelin treatment. We meanwhile confirmed that hexarelin induced down-regulation of IL-1ß expression and up-regulation of IL-1Ra expression in I/R myocardium, which could be neutralized by the GHSR antagonist [D-Lys3]-growth hormone releasing peptide-6 ([D-Lys3]-GHRP-6). These findings suggest that hexarelin protects in vivo cardiomyocytes from I/R injury partly by modification of the IL-1 signaling pathway through the activation of cardiac GHSR1a receptors.

Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions.

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

Growth factors for treating diabetic foot ulcers.

BACKGROUND: Foot ulcers are a major complication of diabetes mellitus, often leading to amputation. Growth factors derived from blood platelets, endothelium, or macrophages could potentially be an important treatment for these wounds but they may also confer risks. OBJECTIVES: To assess the benefits and harms of growth factors for foot ulcers in patients with type 1 or type 2 diabetes mellitus. SEARCH METHODS: In March 2015 we searched the Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised clinical trials in any setting, recruiting people with type 1 or type 2 diabetes mellitus diagnosed with a foot ulcer. Trials were eligible for inclusion if they compared a growth factor plus standard care (e.g., antibiotic therapy, debridement, wound dressings) versus placebo or no growth factor plus standard care, or compared different growth factors against each other. We considered lower limb amputation (minimum of one toe), complete healing of the foot ulcer, and time to complete healing of the diabetic foot ulcer as the primary outcomes. DATA COLLECTION AND ANALYSIS: Independently, we selected randomised clinical trials, assessed risk of bias, and extracted data in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We subjected our analyses to both fixed-effect and random-effects model analyses. MAIN RESULTS: We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor ß2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials.Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I(2) = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I(2) = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I(2)= 74%, five trials).In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I(2) = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence)Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I(2) = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.

Periodontal regeneration - intrabony defects: a systematic review from the AAP Regeneration Workshop.

BACKGROUND: Previous systematic reviews of periodontal regeneration with bone replacement grafts and guided tissue regeneration (GTR) were defined as state of the art for clinical periodontal regeneration as of 2002. METHODS: The purpose of this systematic review is to update those consensus reports by reviewing periodontal regeneration approaches developed for the correction of intrabony defects with the focus on patient-, tooth-, and site-centered factors, surgical approaches, surgical determinants, and biologics. This review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews. A computerized search of the PubMed and Cochrane databases was performed to evaluate the clinically available regenerative approaches for intrabony defects. The search included screening of original reports, review articles, and reference lists of retrieved articles and hand searches of selected journals. All searches were focused on clinically available regenerative approaches with histologic evidence of periodontal regeneration in humans published in English. For topics in which the literature is lacking, non-randomized observational and experimental animal model studies were used. Therapeutic endpoints examined included changes in clinical attachment level, changes in bone level/fill, and probing depth. For purposes of analysis, change in bone fill was used as the primary outcome measure, except in cases in which this information was not available. The SORT (Strength of Recommendation Taxonomy) grading scale was used in evaluating the body of knowledge. RESULTS: 1) Fifty-eight studies provided data on patient, tooth, and surgical-site considerations in the treatment of intrabony defects. 2) Forty-five controlled studies provided outcome analysis on the use of biologics for the treatment of intrabony defects. CONCLUSIONS: 1) Biologics (enamel matrix derivative and recombinant human platelet-derived growth factor-BB plus ß-tricalcium phosphate) are generally comparable with demineralized freeze-dried bone allograft and GTR and superior to open flap debridement procedures in improving clinical parameters in the treatment of intrabony defects. 2) Histologic evidence of regeneration has been demonstrated with laser therapy; however, data are limited on clinical predictability and effectiveness. 3) Clinical outcomes appear most appreciably influenced by patient behaviors and surgical approach rather than by tooth and defect characteristics. 4) Long-term studies indicate that improvements in clinical parameters are maintainable up to 10 years, even in severely compromised teeth, consistent with a favorable/good long-term prognosis.

Avoiding the prenatal programming effects of glucocorticoids: are there alternative treatments for the induction of antenatal lung maturation?

BACKGROUND: The long-term outcomes of antenatal glucocorticoids (GCs) vary between reports, and have generated controversy in terms of repeated and single-course events, causing irreversible effects on endocrine set points. AIM: This study aimed to assess the effects of alternative therapeutic agents other than synthetic glucocorticoid GC administration for fetal lung maturation. METHODS: A review of literature from PubMed, EMBASE, Cochrane Library, and Google Scholar was conducted to assess the use of alternative therapies to synthetic GCs using recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). End points included the rates of respiratory distress syndrome (RDS), mRNA expression for pneumocyte type II, concentration of surfactant proteins in alveolar lavage, morphological differences, histological proof of lung maturation, and angiogenesis or quantification of the surfactant pool. RESULTS: In all 41 studies examined, we found that ambroxol showed positive effects on lung maturation, but it has yet to be analyzed with sufficient significance in humans. Interleukins and TNF-alpha produce accelerated lung maturation, but have only been evaluated in basic research/experimental studies. Growth factors promote structural and functional growth in all phases of lung maturation, but little is known about their reciprocal effects and exact mechanisms as therapeutics. Thyroid releasing hormone or vitamin A cause detrimental side effects or were less effective for lung maturation. CONCLUSIONS: The efficacy and safety of these alternative agents are differentiated and none up to now can be recommended as an alternative to GCs.

The pharmacologic treatment of short bowel syndrome: new tricks and novel agents.

Short bowel syndrome (SBS) is a manifestation of massive resection of the intestines resulting in severe fluid, electrolyte, and vitamin/mineral deficiencies. Diet and parenteral nutrition play a large role in the management of SBS; however, pharmacologic options are becoming more readily available. These pharmacologic agents focus on reducing secretions and stimulating intestinal adaptation. The choice of medication is highly dependent on the patient's symptoms, remaining anatomy, and risk versus benefit profile for each agent. This article focuses on common and novel pharmacologic medications used in SBS, including expert advice on their indications and use.

Cyclophosphamide intoxication because of pharmacy error in two dogs.

CASE DESCRIPTION: An 8-year-old spayed female Yorkshire Terrier and 5-year-old castrated male West Highland White Terrier were evaluated because of cyclophosphamide intoxication subsequent to pharmacy error. Both dogs received cumulative doses of approximately 1,080 mg of cyclophosphamide/m(2) after cyclophosphamide was erroneously dispensed instead of cyclosporine by different pharmacies. CLINICAL FINDINGS: Both dogs became lethargic, and 1 dog also had anorexia, vomiting, and diarrhea within 2 days after initiation of cyclophosphamide administration. The other dog developed anorexia on the seventh day after initiation of cyclophosphamide administration. The dogs were evaluated by their primary-care veterinarians 9 and 11 days after administration of the first dose of cyclophosphamide, and both had severe leukopenia and thrombocytopenia. TREATMENT AND OUTCOME: One dog was treated on an outpatient basis with broad-spectrum antimicrobials, granulocyte colony-stimulating factor, and an appetite stimulant. The other dog was more severely affected and was hospitalized for 7 days, during which it was treated with broad-spectrum antimicrobials, gastroprotectants, granulocyte colony-stimulating factor, and cryopreserved platelet and packed RBC transfusions. Both dogs fully recovered after treatment. CLINICAL RELEVANCE: This was the first report of survival for dogs with inadvertent prolonged cyclophosphamide intoxication subsequent to pharmacy error. Although the 2 dogs had similar clinical signs and clinicopathologic findings, the severity of disease and treatment required differed for each dog. Dogs can recover from prolonged cyclophosphamide intoxication provided appropriate supportive care is administered.

Potential targets in the discovery of new hair growth promoters for androgenic alopecia.

INTRODUCTION: Androgenic alopecia (AGA) is the major type of scalp hair loss affecting 60 - 70% of the population worldwide. It is caused by two potent androgens, namely testosterone (T) and 5α-dihydrotestosterone (5α-DHT). Till date, only two FDA-approved synthetic drugs, minoxidil and finasteride, are used to cure AGA with only 35 and 48% success, respectively; therefore, a search for new drug based on the mechanism of androgens action is still needed. AREAS COVERED: Relevant literature was reviewed to identify current therapeutic targets and treatments for AGA. The potential targets are classified into three categories: i) 5α-reductase; ii) androgen receptor and iii) growth-factor-producing genes related to hair growth. EXPERT OPINION: Relevant assay systems using the right targets are required in order to obtain specific and effective drugs for AGA treatment. It is unlikely that single targeted agents will be sufficient for treating AGA, and therefore, it would be a challenge to obtain compounds with multiple activities.

The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science. STUDY SELECTION: Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention. RESULTS: Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. In random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions. CONCLUSION: Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. The antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.

Impact of IGF-I release kinetics on bone healing: a preliminary study in sheep.

Spatiotemporal release of growth factors from a delivery device can profoundly affect the efficacy of bone growth induction. Here, we report on a delivery platform based on the encapsulation of insulin-like growth factor I (IGF-I) in different poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) microsphere (MS) formulations to control IGF-I release kinetics. In vitro IGF-I release profiles generally exhibited an initial burst (14-36% of total IGF-I content), which was followed by a more or less pronounced dormant phase with little release (2 to 34 days), and finally, a third phase of re-increased IGF-I release. The osteoinductive potential of these different IGF-I PL(G)A MS formulations was tested in studies using 8-mm metaphyseal drill hole bone defects in sheep. Histomorphometric analysis at 3 and 6 weeks after surgery showed that new bone formation was improved in the defects locally treated with IGF-I PL(G)A MS (n=5) as compared to defects filled with IGF-I-free PL(G)A MS (n=4). The extent of new bone formation was affected by the particular release kinetics, although a definitive relationship was not evident. Local administration of IGF-I resulted in down-regulation of inflammatory marker genes in all IGF-I treated defects. The over-expression of growth factor genes in response to IGF-I delivery was restricted to formulations that produced osteogenic responses. These experiments demonstrate the osteoinductive potential of sustained IGF-I delivery and show the importance of delivery kinetics for successful IGF-I-based therapies.

Adipose-derived stem cells combined with neuregulin-1 delivery systems for heart tissue engineering.

Myocardial infarction (MI) is the leading cause of death worldwide, and extensive research has therefore been performed to find a cure. Neuregulin-1 (NRG) is a growth factor involved in cardiac repair after MI. We previously described how biocompatible and biodegradable microparticles, which are able to release NRG in a sustained manner, represent a valuable approach to avoid problems related to the short half-life after systemic administration of proteins. The effectiveness of this strategy could be improved by combining NRG with several cytokines involved in cardiac regeneration. The present study investigates the potential feasibility of using NRG-releasing particle scaffold combined with adipose-derived stem cells (ADSC) as a multiple growth factor delivery-based tissue engineering strategy for implantation in the infarcted myocardium. NRG-releasing particle scaffolds with a suitable size for intramyocardial implantation were prepared by TROMS. Next, ADSC were adhered to particle scaffolds and their potential for heart administration was assessed in a MI rat model. NRG was successfully encapsulated reaching encapsulation efficiencies of 92.58 ± 3.84%. NRG maintained its biological activity after the microencapsulation process. ADSCs adhered efficiently to particle scaffolds within a few hours. The ADSC-cytokine delivery system developed proved to be compatible with intramyocardial administration in terms of injectability through a 23-gauge needle and tissue response. Interestingly, ADSC-scaffolds were present in the peri-infarted tissue 2 weeks after implantation. This proof of concept study provides important evidence required for future effectiveness studies and for the translation of this approach.

Excretion profile of corticosteroids in bovine urine compared with tissue residues after therapeutic and growth-promoting administration of dexamethasone.

The illicit use of dexamethasone as growth-promoting agent in animal breeding is still practiced within the EU constituting a health risk for meat consumers. An experimental study was developed to assess dexamethasone urinary excretion and tissue distribution (liver, kidney, and muscle) in male calves after therapeutic and growth-promoting administration. Urine and tissue samples collected from treated and untreated bovines were also investigated for the presence of other natural and synthetic corticosteroids (prednisolone, prednisone, hydrocortisone, and cortisone), in order to study a possible correlation with dexamethasone administration and to clarify prednisolone origin. Analyses were performed by a multi-residue LC-MS/MS method developed and validated according to the Commission Decision 2002/657/EC. The results confirm the rapid rate of dexamethasone urinary excretion, irrespective of the dosage, the duration and the route of administration, and the disappearance of cortisone and hydrocortisone during the treatment. Dexamethasone was distributed to the tissues where the elimination rate proceeded relatively slower as suggested by the presence of residues one month after the withdrawal of the therapeutic treatment. An increase in the number of positive findings for prednisolone, in association with higher levels of cortisone and hydrocortisone, was observed in urine samples collected from slaughterhouse rather than those collected at the farm. Prednisone residues were found only in one urine sample that showed the highest levels of prednisolone, hydrocortisone, and cortisone. The occurrence of prednisolone residues in urine and even in tissue samples confirms the endogenous nature of this molecule.