The Content of Pre-habilitative Interventions for Patients Undergoing Repair of Abdominal Aortic Aneurysms and Their Effect on Post-Operative Outcomes: A Systematic Review.

OBJECTIVE: Patients requiring abdominal aortic aneurysm (AAA) repair are at risk of post-operative complications due to poor pre-operative state. Pre-habilitation describes the enhancement of functional capacity and tolerance to an upcoming physiological stressor, intended to reduce those complications. The ability to provide such an intervention (physical, pharmacological, nutritional, or psychosocial) between diagnosis and surgery is a growing interest, but its role in AAA repair is unclear. This paper aimed to systematically review existing literature to better describe the effect of pre-habilitative interventions on post-operative outcomes of patients undergoing AAA repair. DATA SOURCES: EMBASE and Medline were searched from inception to October 2020. Retrieved papers, systematic reviews, and trial registries were citation tracked. REVIEW METHODS: Randomised controlled trials (RCTs) comparing post-operative outcomes for adult patients undergoing a period of pre-habilitation prior to AAA repair (open or endovascular) were eligible for inclusion. Two authors screened titles for inclusion, assessed risk of bias, and extracted data. Primary outcomes were post-operative 30 day mortality, composite endpoint of 30 day post-operative complications, hospital length of stay (LOS), and health related quality of life (HRQL) outcomes. The content of interventions was extracted and a narrative analysis of results undertaken. RESULTS: Seven RCTs with 901 patients were included (three exercise based, two pharmacological based, and two nutritional based). Risk of bias was mostly unclear or high and the clinical heterogeneity between the trials precluded data pooling for meta-analyses. The quality of intervention descriptions was highly variable. One exercise based RCT reported significantly reduced hospital LOS and another improved HRQL outcomes. Neither pharmacological nor nutritional based RCTs reported significant differences in primary outcomes. CONCLUSION: There is limited evidence to draw clinically robust conclusions about the effect of pre-habilitation on post-operative outcomes following AAA repair. Well designed RCTs, adhering to reporting standards for intervention content and trial methods, are urgently needed to establish the clinical and cost effectiveness of pre-habilitation interventions.

The potential effects of anabolic-androgenic steroids and growth hormone as commonly used sport supplements on the kidney: a systematic review.

BACKGROUND: Anabolic-androgenic steroids and growth hormone are among the most commonly used supplements by sportsmen and sportswomen. The aim of this systematic review is to collect and report available data about renal safety of anabolic-androgenic steroids and growth hormone (GH). METHODS: The search strategy was in accordance with the PRISMA guideline. Seven databases such as Scopus, Medline, Embase, and ISI Web of Knowledge were searched using keywords, such as "growth hormone", "anabolic-androgenic steroids", and "kidney injury". Articles published from 1950 to December 2017 were considered. Randomized clinical trials, prospective or retrospective human studies, case series as well as case reports, and experimental (in vivo) studies were included. Twenty one clinical and experimental articles were selected (12 for anabolic-androgenic steroids and 9 for GH). RESULTS: Anabolic-androgenic steroids can affect the kidney in different aspects. They can induce or aggravate acute kidney injury, chronic kidney disease, and glomerular toxicity. These adverse effects are mediated through pathways such as stimulating renin-angiotensin-aldosterone system, enhancing the production of endothelin, producing reactive oxygen species, over-expression of pro-fibrotic and pro-apoptotic mediators (e.g., TGF-ß1), as well as inflammatory cytokines (e.g., TNF-α, IL-1b, and IL-6). Although GH may affect the kidney in different aspects, such as size, glomerular filtration rate, and tubule functions, either directly or indirectly, there is no conclusive clinical evidence about its detrimental effects on the kidney in athletes and body builders. CONCLUSION: Evidence regarding effects of anabolic-androgenic steroids exists; However, GH's exact effect on the kidney at doses used by athletes and body builders has not yet been clarified. Cohort clinical studies with long-term follow-up are warranted in this regard.

The diagnosis of cystinosis in patients reveals new CTNS gene mutations in the Chinese population.

Background Cystinosis is a rare autosomal-recessive disorder caused by a defective transport of cystine across the lysosomal membrane. Previous studies have mapped cystinosis to the CTNS gene which is located on chromosome 17p13, and various CTNS mutations have been identified to correlate them with this disease. Methods We analyzed six patients from five unrelated families who were diagnosed with cystinosis in our hospital. We described the diagnostic procedures for all the patients and proposed alternative therapies for cystinosis patients instead of using cysteamine, an orphan drug which was commercially unavailable in China. Moreover, genetic analysis of all patients' samples was carried out to identify novel CTNS gene mutations. Results and conclusions The patients in this study were followed up from 1 to more than 10 years to monitor their growth and development, which indicated that the alternative therapies we used were helpful to ameliorate the complications of the cystinosis patients without cysteamine. Furthermore, by sequencing the patients' genome, we identified novel mutations in the CTNS gene including: c.477C > G (p.S159R), c.274C > T (p.Q92X) and c.680A > T (p.E227V); these mutations were only observed in cystinosis patients and had never been reported in any other populations, suggesting they might be specific to Chinese cystinosis patients.

GH Supplementation Effects on Cardiovascular Risk in GH Deficient Adult Patients: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: The current meta-analysis aims at evaluating whether the existing clinical evidence may ascertain the effects of growth hormone (GH) replacement therapy on cardiovascular risk, both in isolated GH deficiency (GHD) and in compensated panhypopituitarism including GH deficit. METHODS: Original articles published from 1991 to 2015 were searched on Medline (Pubmed). Among an overall number of 181 potentially suitable studies, 24 fulfilled the selection criteria and were included in the analysis. Data aggregation was carried out through the calculation of the absolute risk reduction. The meta-analysis was then conducted by means of a fixed-effects model, according to the heterogeneity test (Chi-square statistic). RESULTS: Fat-free mass (FFM) increase and fat mass (FM) reduction were found, together with a C-LDL reduction, a wide variation in glycaemia and a neutral effect on glycated haemoglobin (HbA1c) and blood pressure. These effects were valid both for isolated GHD patients and for those with compensated panhypopituitarism. The global outcome D showed a nonsignificant reduction of the overall cardiovascular risk (0.53; 95% C.I. -1.23, 2.85). CONCLUSION: Our meta-analysis shows no signnificatly positive trend in cardiovascular risk after both short and long-term GH supplementation therapy in adult GHD patients. However, a reduction of LDL cholesterol levels has been found. No differences were found between isolated GHD participants and those affected by panhypopituitarism well compensated since at least 3 months.

Supra-physiological rhGH administration induces gender-related differences in the hypothalamus-pituitary-thyroid (HPT) axis in healthy individuals.

PURPOSE: The use of recombinant human growth hormone (rhGH) is a common habit among athletes. While the effects of rhGH administration have been described with contrasting results in males, no data exist in females to date. The aim of the present study was to evaluate the effects of rhGH administration on TSH, FT4 and FT3 levels and the time requested to return to baseline values after treatment withdrawal. METHODS: Twenty-one healthy trained male and female athletes were treated with 0.03 mg rhGH/kg body mass 6 days/week for 3 weeks. We collected blood samples immediately before the first daily rhGH administration, at 3, 4, 8, 15 and 21 days of treatment and at 3 and 9 days after rhGH withdrawal. RESULTS: In males, rhGH administration induced a significant (p < 0.01) early and stable TSH decrease and IGF-I increase, and a delayed FT4 reduction without FT3 modification, suggesting a central regulatory mechanism. In females, rhGH administration induced a significant (p < 0.01) early and transient TSH decrease and IGF-I increase, and a transient reduction in FT4 without any changes in FT3 concentrations. rhGH withdrawal was associated with a prompt normalization of TSH and FT4 levels in males, while in females the effects of rhGH treatment had already disappeared during the last period of treatment. CONCLUSION: We suggest that rhGH inhibits TSH at central level both in males and females. The pattern of normalization was different in the two genders probably due to gonadal steroids modulation on GH-IGF-I axis.

Netnography of Female Use of the Synthetic Growth Hormone CJC-1295: Pulses and Potions.

BACKGROUND: Communal online folk pharmacology fuels the drive for short cuts in attaining muscle enhancement, fat loss, and youthful skin. OBJECTIVES: The study used "netnography" to explore female use of CJC-1295, a synthetic growth hormone analogue from the perspectives contained in Internet forum activity. METHODS: A systematic Internet search was conducted using variation of the term "CJC-1295"; and combined with "forum." Ninety-six hits related to bodybuilding websites where CJC-1295 was mentioned. Following application of exclusion criteria to confine to female use and evidence of forum activity, 9 sites remained. These were searched internally for reference to CJC-1295. Twenty-three discussion threads relating to female use of CJC-1295 formed the end data set, and analyzed using the Empirical Phenomenological Psychological method. RESULTS: Forum users appeared well versed and experienced in the poly use of performance and image drug supplementation. Choice to use CJC-1295 centered on weight loss, muscle enhancement, youthful skin, improved sleep, and injury healing. Concerns were described relating to female consequences of use given gender variations in growth hormone pulses affecting estimation of dosage, cycling, and long-term consequences. CONCLUSIONS: Public health interventions should consider female self-medicating use of synthetic growth hormone within a repertoire of product supplementation, and related adverse health consequences.

Adipokine zinc-α2-glycoprotein regulated by growth hormone and linked to insulin sensitivity.

OBJECTIVE: Hypertrophic obesity is associated with impaired insulin sensitivity and lipid-mobilizing activity of zinc-α2-glycoprotein. Adipose tissue (AT) of growth hormone (GH) -deficient patients is characterized by extreme adipocyte hypertrophy due to defects in AT lipid metabolism. It was hypothesized that zinc-α2-glycoprotein is regulated by GH and mediates some of its beneficial effects in AT. METHODS: AT from patients with GH deficiency and individuals with obesity-related GH deficit was obtained before and after 5-year and 24-month GH supplementation therapy. GH action was tested in primary human adipocytes. Relationships of GH and zinc-α2-glycoprotein with adipocyte size and insulin sensitivity were evaluated in nondiabetic patients with noncancerous cachexia and hypertrophic obesity. RESULTS: AT in GH-deficient adults displayed a substantial reduction of zinc-α2-glycoprotein. GH therapy normalized AT zinc-α2-glycoprotein. Obesity-related relative GH deficit was associated with almost 80% reduction of zinc-α2-glycoprotein mRNA in AT. GH increased zinc-α2-glycoprotein mRNA in both AT of obese men and primary human adipocytes. Interdependence of GH and zinc-α2-glycoprotein in regulating AT morphology and metabolic phenotype was evident from their relationship with adipocyte size and AT-specific and whole-body insulin sensitivity. CONCLUSIONS: The results demonstrate that GH is involved in regulation of AT zinc-α2-glycoprotein; however, the molecular mechanism linking GH and zinc-α2-glycoprotein in AT is yet unknown.

Consensus document of the Neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition on management of hypopituitarism during transition.

The transition period from child to adult represents a crucial phase in the growth process where multiple physical and psychosocial changes occur. It has been arbitrarily defined as the period extending from late puberty to full adult maturity (i.e., from mid to late teenage years until 6-7 years after achievement of final height). The aim of this guideline is to emphasize the importance of adequate hormone replacement during this period and to review reassessment of pituitary function. In patients with GH deficiency diagnosed in childhood, an attempt is made to answer when to retest GH secretion, when to treat and how they should be monitored. Thyroxine, glucocorticoid, and sex steroid replacement are also reviewed.

Evaluation of the bioefficacy of a stabilized form of human growth hormone (SP-hGH).

Protein aggregation is a major obstacle in maintaining the stability of therapeutic proteins. In previous studies, fusion between a stabilizing peptide (SP) and human growth hormone (hGH) resulted in improved solubility and stability compared with hGH alone, although the bioactivity of the protein was not confirmed in vivo. In this study, we evaluated the bioefficacy of hGH and SP-hGH in vivo using a mouse model. Subcutaneous injections of 30 µg of hGH or SP-hGH were administered to 8-month-old female mice, twice a week for 14 weeks. Neither hGH nor SP-hGH significantly affected body weight or blood glucose levels compared with control mice. Interestingly, abdominal fat was significantly reduced in SP-hGH-treated mice compared with hGH-treated mice. While total cholesterol, HDL, and LDL levels were slightly higher in both groups, TG levels were significantly reduced in both SP-hGH and hGH-treated mice compared with control mice. IGF-1 levels in the liver were increased in both the SP-hGH and hGH groups, thereby inducing liver cell proliferation. These results suggest that SP fusion with hGH attained similar or improved bioefficacy compared with hGH alone.

Effect of growth hormone on dawn phenomenon in patients with type 2 diabetes.

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.

Topical application of melatonin and growth hormone accelerates bone healing around dental implants in dogs.

BACKGROUND: Growth hormone (GH) and melatonin belong to the group of growth factors. These substances have been proposed to improve and accelerate osseous healing using topical applications. PURPOSE: The aim of this study was to evaluate the effect of the topical administration of GH and melatonin on osseointegration of dental implants in Beagle dogs 2, 5, and 8 weeks after their insertion. MATERIALS AND METHODS: Twelve adult Beagle dogs and 48 implants were used in the study. The maxillary and mandibular premolars and molars were extracted. Each mandible received cylindrical screw implants of 3.25 mm in diameter and 10 mm in length. Prior to implanting, 4 IU of recombinant human GH and 1.2 mg of lyophilized powdered melatonin was applied to one osteotomy at each side of the mandible. None was applied at the control sites. The implants were retrieved at 2, 5, and 8 weeks for light microscopic examination, energy-dispersive x-ray microanalysis, and histomorphometric measurements in ground sections. RESULTS: At week 2, BIC was significantly higher in the melatonin-growth hormone group than in the implant control one (34.20 vs 25.05%; p = .010). The M-GH group also increased significantly the peri-implant bone area (64.72 vs 53.20%; p = .038) and interthread bone area (35.62 vs 25.08%; p = .02). At weeks 5 and 8, BIC and bone density around implants were similar to both groups. Significant differences were detected in bone neoformation at 8 weeks in ML-GH group (9.04 vs 7.53%; p = .05). Regarding the mineral composition, in ML-GH group increments in concentrations of phosphorus (10.70 vs 10.34; p = .013) were observed at 2 weeks and of magnesium (0.29 vs 0.25; p = .019) 5 weeks after implantation. CONCLUSION: The present study confirms that GH and melatonin synergistically enhance new bone formation around titanium implants in early stages of healing.

OMICS-strategies and methods in the fight against doping.

During the past decade OMICS-methods not only continued to have their impact on research strategies in life sciences and in particular molecular biology, but also started to be used for anti-doping control purposes. Research activities were mainly reasoned by the fact that several substances and methods, which were prohibited by the World Anti-Doping Agency (WADA), were or still are difficult to detect by direct methods. Transcriptomics, proteomics, and metabolomics in theory offer ideal platforms for the discovery of biomarkers for the indirect detection of the abuse of these substances and methods. Traditionally, the main focus of transcriptomics and proteomics projects has been on the prolonged detection of the misuse of human growth hormone (hGH), recombinant erythropoietin (rhEpo), and autologous blood transfusion. An additional benefit of the indirect or marker approach would also be that similarly acting substances might then be detected by a single method, without being forced to develop new direct detection methods for new but comparable prohibited substances (as has been the case, e.g. for the various forms of Epo analogs and biosimilars). While several non-OMICS-derived parameters for the indirect detection of doping are currently in use, for example the blood parameters of the hematological module of the athlete's biological passport, the outcome of most non-targeted OMICS-projects led to no direct application in routine doping control so far. The main reason is the inherent complexity of human transcriptomes, proteomes, and metabolomes and their inter-individual variability. The article reviews previous and recent research projects and their results and discusses future strategies for a more efficient application of OMICS-methods in doping control.

Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone.

BACKGROUND: There are limited long-term randomized controlled trials of growth hormone (GH) supplementation to adult height and few published reports of the health-related quality of life (HRQOL) following treatment. The present follow-up study of young adults from a long-term controlled trial of GH treatment in patients with Turner syndrome (TS) yielded data to examine whether GH supplementation resulted in a higher HRQOL (either due to taller stature or from the knowledge that active treatment and not placebo had been received) or alternatively a lower HRQOL (due to medicalization from years of injections). METHODS: The original trial randomized 154 Canadian girls with TS aged 7-13 years from 13 centres to receive either long-term GH injections at the pharmacologic dose of 0.3 mg/kg/week or to receive no injections; estrogen prescription for induction of puberty was standardized. Patients were eligible for the follow-up study if they were at least 16 years old at the time of follow-up. The instrument used to study HRQOL was the SF-36, summarized into physical and mental component scales (PCS and MCS); higher scores indicate better HRQOL. RESULTS: Thirty-four of the 48 eligible participants (71%) consented to participate; data were missing for one patient. Both groups (GH and no treatment) had normal HRQOL at this post-treatment assessment. The GH group had a (mean ± SD) PCS score of 56 ± 5; the untreated group 58 ± 4; mean score for 16-24 year old females in the general population 53.5 ± 6.9. The GH group had a mean MCS score of 52 ± 6; the untreated group 49 ± 13; mean score for 16-24 year old females in the general population 49.6 ± 9.8. Secondary analyses showed no relationship between HRQOL and height. CONCLUSIONS: We found no benefit or adverse effect on HRQOL either from receiving or not receiving growth hormone injections in a long-term randomized controlled trial, confirming larger observational studies. We suggest that it remains ethically acceptable as well as necessary to maintain a long-term untreated control group to estimate the effects of pharmacological agents to manipulate adult height. Young adult women with TS have normal HRQOL suggesting that they adjust well to their challenges in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00191113.

Durability of the effects of testosterone and growth hormone supplementation in older community-dwelling men: the HORMA Trial.

OBJECTIVES: To determine the durability of anabolic effects and adverse events (AEs) after stopping testosterone and growth hormone supplementation in older men. DESIGN: Secondary analysis of a double-masked, randomized controlled trial of testosterone gel (5 or 10 g/daily) plus rhGH (0, 3 or 5 µg/kg/day) with follow-up of outcomes 3 months later. PARTICIPANTS: A total of 108 community-dwelling 65- to 90-year-old men. MEASUREMENTS: Testosterone and IGF-1 levels, body composition (DEXA), 1-repetition maximum (1-RM) strength, stair-climbing power, quality-of-life (QOL) and activity questionnaires, AEs. RESULTS: Despite improvements in body composition during treatment, residual benefits 3 months later (week 28) were variable. For participants with improvements exceeding their week-17 median changes, benefits were sustained at week 28 for lean body mass (1·45 ± 1·63 kg, 45% of week-17 values, P < 0·0001 vs baseline), appendicular skeletal muscle mass (ASMM, 0·71 ± 1·01 kg, 42%, P < 0·0001), total fat (-1·06 ± 2·18 kg, 40%, P < 0·0001) and trunk fat (-0·89 ± 1·42 kg, 50%, P < 0·0001); retention of ASMM was associated with greater week-16 protein intake (P = 0·01). For 1-RM strength, 39%-43% of week-17 improvements (P ≤ 0·05) were retained and associated with better week-17 strength (P < 0·0001), change in testosterone from week 17-to 28 (P = 0·004) and baseline PASE (P = 0·04). Framingham 10-year cardiovascular risks were low (~14%), did not worsen and improved by week 28 (P = 0·0002). The hypothalamic-pituitary-gonadal axis recovered completely. CONCLUSIONS: Durable improvements in muscle mass, strength and fat mass were retained 3 months after discontinuing hormone supplementation in participants with greater than median body composition changes during treatment, but not in others with smaller gains. AEs largely resolved after intervention discontinuation. Additional strategies may be needed to sustain or augment muscle mass and strength gains achieved during short-term hormone therapy.

Hypothalamic involvement and insufficient sex steroid supplementation are associated with low bone mineral density in women with childhood onset craniopharyngioma.

CONTEXT: Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)-craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment. OBJECTIVE: The aims were to evaluate BMD in adults with CO-CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures. DESIGN AND PARTICIPANTS: BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO-CP adults (20 women), with a median age of 28 (17-57) years, in comparison with matched population controls. RESULTS: Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (P=0.03) at L2-L4, and reduced Z-scores at femoral neck (P=0.004) and L2-L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2-L4 (P=0.003; r=-0.5) and 45% of CP women had Z-score levels ≤-2.0 s.d. Furthermore, 75% of those with a Z-score ≤-2.0 s.d. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only. CONCLUSIONS: Despite continuous GH therapy, low BMD was recorded in CO-CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.

Effects of growth hormone and nutritional therapy in boys with constitutional growth delay: a randomized controlled trial.

OBJECTIVE: To examine whether supplemental nutrition augments the anabolic actions of growth hormone (GH) in boys with constitutional delay of growth and maturation (CDGM). STUDY DESIGN: We conducted a randomized, controlled trial at an outpatient clinical research center. Subjects were 20 prepubertal boys (age, 9.3 ± 1.3 years) with CDGM (height standard deviation score, -2.0 ± 0.5; bone age delay, 1.8 ± 0.8 years; body mass index standard deviation score, -1.2 ± 1.0; peak stimulated GH, 15.7 ± 7.7 ng/mL), who were randomized (n = 10/group) to 6 months observation or daily nutritional supplementation, followed by additional daily GH therapy in all for another 12 months. t tests and repeated measures analyses of variance compared energy intake, total energy expenditure (TEE), growth, hormones, and nutrition markers. RESULTS: Energy intake was increased at 6 months within the nutrition group (P = .04), but not the observation group, and TEE was not statistically different within either group at 6 months. Addition of 6 months GH resulted in higher energy intake and TEE in the GH/nutrition group at 12 months (P < .01), but not in the GH group versus baseline. Height, weight, lean body mass, hormones, and nutrition markers increased comparably in both groups throughout 18 months. CONCLUSION: Boys with CDGM use energy at an accelerated rate, an imbalance not overcome with added nutrition. GH therapy increases growth comparably with or without added nutrition in these patients.

[Growth hormone revisited]. / Hormona de crecimiento: acciones y aplicaciones preventivas y terapéuticas.

Growth hormone (GH) is a pleiotropic hormone, expressed at pituitary and peripheral level, which plays a number of different roles far beyond of those classically described. Among these effects it is remarkable the neurotropic role of GH: the hormone increases the proliferation and survival of neural precursors in response to neurological injuries. At the cardiovascular level, GH improves the lipidic profile and decreases the factors of cardiac risk; the hormone recovers the endothelial function, improves the cardiac function and potentiates revascularisation in ischemic territories. Differently to that occurring with autocrine GH, exogenous GH administration does not seem to be related to oncogenesis. According to its effects, there are multiple potential clinical applications of GH: acute treatment of brain injury, due to its antiapoptotic effect; central or peripheral neural regeneration; acute treatment of perinatal anoxia, prevention cerebral palsy; revascularisation of ischemic areas; decrease of the time of bone consolidation after a bone fracture; and torpid ulcer healing.