Growth arrest-specific protein-6/AXL signaling induces preeclampsia in rats†.

Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure, decreased trophoblast invasion, and inflammation. The growth arrest-specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. Gas6 binds to the AXL tyrosine kinase receptor and AXL-mediated signaling is implicated in proliferation and migration observed in several tissues. Our laboratory utilized Gas6 to induce preeclamptic-like conditions in pregnant rats. Our objective was to determine the role of Gas6/AXL signaling as a possible model of PE. Briefly, pregnant rats were divided into three groups that received daily intraperitoneal injections (from gestational day 7.5 to 17.5) of phosphate buffered saline (PBS), Gas6, or Gas6 + R428 (an AXL inhibitor administered from gestational day 13.5 to 17.5). Animals dispensed Gas6 experienced elevated blood pressure, increased proteinuria, augmented caspase-3-mediated placental apoptosis, and diminished trophoblast invasion. Gas6 also enhanced expression of several PE-related genes and a number of inflammatory mediators. Gas6 further enhanced placental oxidative stress and impaired mitochondrial respiration. Each of these PE-related characteristics was ameliorated in dams and/or their placentae when AXL inhibition by R428 occurred in tandem with Gas6 treatment. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL prevents disease progression in pregnant rats. These results provide insight into pathways associated with PE that could be useful in the clarification of potential therapeutic approaches.

Plasma Rich in Growth Factors (PRGF) Disrupt the Blood-Brain Barrier Integrity and Elevate Amyloid Pathology in the Brains of 5XFAD Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting 5.4 million people in the United States. Currently approved pharmacologic interventions for AD are limited to symptomatic improvement, not affecting the underlying pathology. Therefore, the search for novel therapeutic strategies is ongoing. A hallmark of AD is the compromised blood-brain barrier (BBB); thus, developing drugs that target the BBB to enhance its integrity and function could be a novel approach to prevent and/or treat AD. Previous evidence has shown the beneficial effects of growth factors in the treatment of AD pathology. Based on reported positive results obtained with the product Endoret®, the objective of this study was to investigate the effect of plasma rich in growth factors (PRGF) on the BBB integrity and function, initially in a cell-based BBB model and in 5x Familial Alzheimer's Disease (5xFAD) mice. Our results showed that while PRGF demonstrated a positive effect in the cell-based BBB model with the enhanced integrity and function of the model, the in-vivo findings showed that PRGF exacerbated amyloid pathology in 5xFAD brains. At 10 and 100% doses, PRGF increased amyloid deposition associated with increased apoptosis and neuroinflammation. In conclusion, our results suggest PRGF may not provide beneficial effects against AD and the consideration to utilize growth factors should further be investigated.

Injury, repair, inflammation and metaplasia in the stomach.

The development of intestinal-type gastric cancer is preceded by the emergence of metaplastic cell lineages in the gastric mucosa. In particular, intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) have been associated with the pathological progression to intestinal-type gastric cancer. The development of SPEM represents a physiological response to damage that recruits reparative cells to sites of mucosal injury. Metaplastic cell lineages are characterized by mucus secretion, adding a protective barrier to the epithelium. Increasing evidence indicates that the influence of alarmins and cytokines is required to initiate the process of metaplasia development. In particular, IL-33 derived from epithelial cells stimulates IL-13 production by specialized innate immune cells to induce chief cell transdifferentiation into SPEM following the loss of parietal cells from the corpus of the stomach. While SPEM represents a physiological healing response to acute injury, persistent injury and chronic inflammation can perpetuate a recurring pattern of reprogramming and metaplasia that is a risk factor for gastric cancer development. The transdifferentiation of zymogen secreting cells into mucous cell metaplasia may represent both a general repair mechanism in response to mucosal injury in many epithelia as well as a common pre-neoplastic pathway associated with chronic injury and inflammation.

Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease.

OBJECTIVES: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. METHODS: In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. RESULTS: Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. CONCLUSIONS: Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. TRIAL REGISTRATION NUMBER: NCT02398435.

Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp.

AIMS: Apelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans. MATERIALS AND METHODS: Healthy overweight men were enrolled in this randomized, double-blind, placebo-controlled, cross-over study that successively considered the efficacy and the tolerance of 2 doses of (pyr1)-Apelin-13. A first group of subjects received 9 nmol/kg (n = 8) of (pyr1)-Apelin-13 and, after examination of safety data, a second group received 30 nmol/kg (n = 8). Each volunteer underwent 2 hyperinsulinaemic-euglycaemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minute (level 1). Continuous intravenous administration of apelin or placebo was ongoing for 2 hours and GIR was finally evaluated from the 210th to the 240th minute (level 2). Primary evaluation endpoint was the difference in GIR between level 2 and level 1 (ΔGIR). RESULTS: A slight increase in ΔGIR was observed with the low apelin dose (0.65 ± 0.71 mg/kg/min, P = .055) whereas the highest dose significantly improved insulin sensitivity (0.82 ± 0.71 mg/kg/min, P = .033). Cardiovascular monitoring and safety reports did not reveal any side effect of apelin administration. CONCLUSION: As the first demonstration of the insulin-sensitizing action of apelin in humans, alongside numerous studies in rodents, this trial confirms that the apelin/APJ pathway should be considered as a new target to design alternative therapeutic strategies to control insulin resistance in type 2 diabetic patients.

Beneficial long-term antidiabetic actions of N- and C-terminally modified analogues of apelin-13 in diet-induced obese diabetic mice.

AIMS: To investigate the chronic effects of twice-daily administration of stable apelin analogues, apelin-13 amide and pyroglutamyl (pGlu) apelin-13 amide, on metabolic variables in glucose-intolerant and insulin-resistant diet-induced obese mice fed a high-fat diet for 150 days. METHODS: Groups of mice received twice-daily (9 am and 5 pm) injections of saline vehicle, apelin-13 amide, (pGlu)apelin-13 amide or exendin-4(1-39) for 28 days (all at 25 nmol/kg). Energy intake, body weight, non-fasting blood glucose, plasma insulin, glucose tolerance, metabolic response to feeding and insulin sensitivity, together with pancreatic hormone content and biochemical variables such as lipids and total GLP-1 were monitored. Dual-energy X-ray absorptiometry analysis and indirect calorimetry were also performed. RESULTS: Administration of apelin-13 amide, (pGlu)apelin-13 amide or exendin-4 significantly decreased body weight, food intake and blood glucose and increased plasma insulin compared with high-fat-fed saline-treated controls (P < .05 and P < .001), Additionally, all peptide-treated groups exhibited improved glucose tolerance (oral and intraperitoneal), metabolic responses to feeding and associated insulin secretion. (pGlu)apelin-13 amide also significantly improved glycated haemoglobin and insulin sensitivity after 28 days. Both (pGlu)apelin-13 amide and exendin-4 increased bone mineral content and decreased respiratory exchange ratio, whereas only (pGlu)apelin-13 amide increased energy expenditure. All treatment groups displayed reduced circulating triglycerides and increased glucagon-like peptide-1 concentrations, although only (pGlu)apelin-13 amide significantly reduced LDL cholesterol and total body fat, and increased pancreatic insulin content. CONCLUSION: These data indicate the therapeutic potential of stable apelin-13 analogues, with effects equivalent to or better than those of exendin-4.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities.

Podocyte injuries are associated with progression of diabetic nephropathy (DN). Apelin, an adipocyte-derived peptide, has been reported to be a promoting factor for DN. In this study, we aim to determine whether apelin promotes progression of DN by inducing podocyte dysfunction. kk-Ay mice were used as models for DN. Apelin and its antagonist, F13A were intraperitoneally administered for 4 weeks, respectively. Renal function and foot process proteins were analysed to evaluate the effects of apelin on kk-Ay mice and podocytes. Apelin increased albuminuria and decreased podocyte foot process proteins expression in kk-Ay mice, which is consistent with the results that apelin receptor (APLNR) levels increased in glomeruli of patients or mice with DN. In cultured podocytes, high glucose increased APLNR expression and apelin administration was associated with increased permeability and decreased foot process proteins levels. All these dysfunctions were associated with decreased 26S proteasome activities and increased polyubiquitinated proteins in both kk-Ay mice and cultured podocytes, as demonstrated by 26S proteasome activation with cyclic adenosine monophosphate (cAMP) or oleuropein. These effects seemed to be related to endoplasmic reticulum (ER) stress, as apelin increased C/EBP homologous protein (CHOP) and peiFα levels while cAMP or oleuropein reduced it in high glucose and apelin treated podocytes. These results suggest that apelin induces podocyte dysfunction in DN through ER stress which was induced by decreased proteasome activities in podocytes.

Pilot, Multicenter, Open-Label Evaluation of Safety, Tolerability and Efficacy of a Novel, Topical Multipotent Growth Factor Formulation for the Periorbital Region.

BACKGROUND: This multicenter, open-label pilot study evaluated safety, efficacy and tolerability of a topical formulation containing a multipotent growth factor resignaling complex (MRCx), when applied to infraorbital and lateral canthal skin. METHODS: Thirty-nine female subjects with mean age of 56.8 years who had periorbital lines and wrinkles, uneven skin texture, puffiness, and lack of skin firmness were enrolled, and 38 completed the study. All subjects applied the multipotent growth factor formulation bilaterally to the periorbital area, twice daily for 60 days. Efficacy and treatment-related adverse events were evaluated at Baseline and days 14, 30, and 60. Investigators rated the periorbital areas based on 10-point scales. RESULTS: Subjects' self-reported compliance with treatment was greater than 99% throughout the study. At day 60, all subjects had improvement in infraorbital brightness (≥ 2 points), moistness (≥ 2 points), wrinkles (≥ 1 point), sallowness (≥ 1 point), crepiness (≥ 1 point), smooth texture (≥ 1 point), skin tightness (≥ 1 point), and skin tone (≥ 1 point). Investigator-rated assessments showed ≥ 1-point improvement for lateral canthal wrinkles, dyschromia/mottled pigmentation, skin tone, overall brightness, and moistness. Investigator-rated scoring on the Global Aesthetic Improvement Scale (GAIS) demonstrated that 67.6% of subjects were much improved/improved at day 14, and 63.1% remained improved at day 60. Overall, 76.2% and 79.0% of subjects were very pleased/pleased/mostly pleased with the appearance of their infraorbital and lateral canthal areas at day 60. Adverse events comprised one case of mild canthal erythema, and one case of mild eye irritation, both of which were respectively resolved. CONCLUSIONS: This pilot study demonstrated that the topical multipotent growth factor formulation was safe, effective and well tolerated for periorbital skin rejuvenation.

The potential of topical and injectable growth factors and cytokines for skin rejuvenation.

Growth factors and cytokines (referred to collectively hereafter as GFs) control cell growth, proliferation, and differentiation via a network of inter and intracellular signaling pathways. There are striking parallels between the pathways involved in skin wound healing and those implicated in photoaging of the skin. In recent years, topical and injectable GFs have emerged as an intriguing therapeutic modality that can be harnessed for aesthetic and medical purposes. This article provides a review of available evidence for the role in skin regeneration of topical GFs, and of injectable GFs contained in autologous platelet-rich plasma (PRP). It presents data from recent studies of GFs, offers a discussion of their potential to serve as antiaging actives, and includes safety considerations. As studies of injectable GFs typically assume preexisting familiarity with PRP protocols and the theory behind them, explanatory notes are provided. An assessment is provided of the evidence gaps that exist currently between experimental observations regarding GFs and their proven clinical benefits. Data of evidence levels II and III support the use for skin rejuvenation of topical GFs derived from sources including secretions or lysate of human dermal fibroblasts, and secretions of the snail Cryptomphalus aspersa. GFs with associated stem cell proteins, secreted by human dermal fibroblasts under hypoxic stress, can accelerate skin healing after laser resurfacing. In vitro and animal studies, small case series of PRP-treated patients and one prospective clinical study of its variant, platelet-rich fibrin matrix (PRFM), suggest the value of injectable GFs for skin rejuvenation. However, data of higher power are required to expand this proof of concept into an evidence-based paradigm. The clinical applications of topical and injectable GFs are promising, and remain to be fully defined. With continued study, data of higher evidence level can be accrued and formulations can be developed that offer optimal clinical efficacy, safety, tolerability, and stability. Better understanding of the mechanism of action of GFs can potentially advance our general understanding of dermal signaling pathways, and hence of hyaluronic acid and other alloplastic fillers; and allow the development of protocols for synergistic combination of GFs with other skin rejuvenation modalities.

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this project was to review the literature and define clinical practice guidelines for the use of cytokines and growth factor agents for the prevention or treatment of oral mucositis induced by cancer chemotherapy or radiotherapy. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible. RESULTS: Sixty-four clinical studies across 11 interventions were evaluated. A recommendation was made for the use of recombinant human KGF-1 (palifermin) at a dose of 60 µg/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplant for prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. A suggestion was made against using granulocyte macrophage colony-stimulating factor mouthwash for the prevention of oral mucositis in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. No guideline was possible for any other cytokine or growth factor agents due to inconclusive evidence. CONCLUSIONS: Of the cytokine and growth factor agents studied for oral mucositis, the evidence only supports use of palifermin in the specific population listed above. Additional well-designed research is needed on other cytokine and growth factor interventions and in other cancer treatment settings.

Therapeutic potential of growth factors in pulmonary emphysematous condition.

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by progressive destruction of alveolar parenchyma with persistent inflammation of the small airways. Such destruction in the distal respiratory tract is irreversible and irreparable. All-trans-retinoic acid was suggested as a novel therapy for regeneration of lost alveoli in emphysema. However, profound discrepancies were evident between studies. At present, no effective therapeutic options are available that allow for the regeneration of lost alveoli in emphysematous human lungs. Recently, some reports on rodent's models have suggested the beneficial effects of various growth factors toward alveolar maintenance and repair processes.

Comparison of intra-articular injections of plasma rich in growth factors (PRGF-Endoret) versus Durolane hyaluronic acid in the treatment of patients with symptomatic osteoarthritis: a randomized controlled trial.

PURPOSE: The purpose of this study was to compare the efficacy and safety in a randomized, clinical trial of 3 injections of PRGF-Endoret (BTI Biotechnology Institute, Vitoria, Spain) versus one single intra-articular injection of Durolane hyaluronic acid (HA) (Q-MED AB, Uppsala, Sweden) as a treatment for reducing symptoms in patients with knee osteoarthritis (OA). METHODS: Ninety-six patients with symptomatic knee OA were randomly assigned to receive PRGF-Endoret (3 injections on a weekly basis) or one infiltration with Durolane HA. The primary outcome measures were a 30% decrease and a 50% decrease in the summed score for the pain, physical function, and stiffness subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne scores from baseline to weeks 24 and 48. The percentage of OMERACT-OARSI (Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative) responders was also documented. As secondary outcomes, pain, stiffness, and physical function by use of the WOMAC and the Lequesne score were considered and overall safety of the injection themselves. RESULTS: The mean age of the patients was 63.6 years. Treatment with PRGF-Endoret was significantly more efficient than treatment with Durolane HA in reducing knee pain and stiffness and improving physical function in patients with knee OA. The rate of response to PRGF-Endoret was significantly higher than the rate of response to HA for all the scores including pain, stiffness, and physical function on the WOMAC, Lequesne index, and OMERACT-OARSI responders at 24 and 48 weeks. Adverse events were mild and evenly distributed between the groups. CONCLUSIONS: Our findings show that PRGF-Endoret is safe and significantly superior to Durolane HA in primary and secondary efficacy analysis both at 24 and 48 weeks; provides a significant clinical improvement, reducing patients' pain and improving joint stiffness and physical function with respect to basal levels in patients with knee OA; and should be considered in the treatment of patients with knee OA.

Drug-related cardiac valve disease.

Cardiac valve disease can involve one or more of the four heart valves. Chronic valve damage may remain asymptomatic for long periods but ultimately leads to haemodynamic overload of the heart. The most common causes of valve disease are rheumatic diseases, infections, chronic renal failure, malformations, and genetic diseases. Valve disease is often attributed to degeneration with no known cause.The frequency of drug-related valve disease has long been underestimated. Most implicated drugs have serotonergic properties, such as fenfluramine-derived amphetamines, including benfluorex. Rye ergot derivatives can also be implicated: these include dopamine agonists (bromocriptine, lisuride, pergolide and cabergoline), migraine treatments (methysergide, ergotamine and dihydroergotamine), and drugs used for cognitive and neurosensory deficits (nicergoline, dihydroergocryptine, etc.). "Ecstasy", an amphetamine, is sometimes also involved. The risk increases after a few months of exposure. Drug withdrawal is sometimes followed by an improvement. Patients exposed to a drug known to cause valve damage should be informed of the risk and receive long-term monitoring to detect these lesions before they become irreversible. The possible role of a drug should always be considered when cardiac valve disease is diagnosed, in order to facilitate active research and to avoid exposing other patients to this risk.

Topical growth factor preparations for facial skin rejuvenation: A systematic review.

BACKGROUND: Cosmeceutical preparations containing growth factors (GFs) are widely used for facial rejuvenation. OBJECTIVE: We performed a systematic review to assess the evidence regarding their safety and effectiveness for facial rejuvenation. METHODS: Electronic databases (Cochrane Library, EMBASE, MEDLINE, and Scopus) were searched from 2000 to October 2022 for prospective trials and case series assessing topical GF preparations for facial rejuvenation in 10 or more participants. RESULTS: Thirty-three studies, including 9 randomized controlled trials (RCTs) and 24 uncontrolled case series, representing 1180 participants receiving 23 different topical preparations containing GFs met the inclusion criteria and were included. Of the 33 studies, nine used a placebo or active control. The GF preparations were applied twice daily in all except two studies, with a mean treatment duration of 3 months. Based on the investigator's assessment, preparations containing GFs induce a modest improvement in skin texture (median < 50%), fine lines/wrinkles (median < 35%), and overall facial appearance (median < 20%) versus baseline. Participant-assessed improvement was generally higher than investigator-assessed response. Three comparative RCTs showed no statistically significant differences between treatments. Studies were limited by heterogeneity with regard to the source and number of GFs used in the preparations, information about additional ingredients, and lack of standardization in the outcome measures. The preparations were associated with a low risk of adverse events. The persistence of the clinical improvements beyond 6 months is not known. CONCLUSIONS: Administration of topical preparations containing GFs appears to be effective for facial skin rejuvenation, as demonstrated by the investigator- and participant-reported outcome measures.

Lysosomes, growth factor activity, and carcinogenic implications.

The aim of this paper is to point out a body of literature which up to now has been largely ignored by investigators in the area of growth factors This paper will offer a response to the questions: Why is it that inhibition of endolysosomal proteases (by agents such as leupeptin, methylamine, etc.) or inhibition of endocytosis block the activities of all growth factors and carcinogens so far studied? What role therefore can endocytosis and endolysosomes (E/L) play in the signal transduction process? As will be detailed below, in many cases involving growth factors, inhibition of E/L proteases results in complete or very significant loss of growth factor activity. That is, treatment with inhibitors of E/L proteases (i.e., leupeptin, antipain methylamine, etc.) erases the normal activity of growth factors affecting systems of concern to immunologists, endocrinologists, and cardiologists. There are strong indications in the literature that suggest that in the nervous system (of obvious interest to neuroscientists) endocytosis plays a vital role in the induced proliferation of neurons as well (of interest to neurologists). This paper will explore the implications and offer an explanation for these findings. Thus this communication will travel from one growth factor to another in order to demonstrate the universality of the model offered in this paper.

When and how should new technology be introduced into the IVF laboratory?

There are many examples in assisted reproduction technology, where new technology and methods have been introduced into the clinical setting without appropriate development and evidence-based medicine to show that the procedure is safe and beneficial to the patient. Examples include preimplantation genetic screening, assisted hatching, in vitro maturation, blastocyst transfer and vitrification. Changes to culture media composition, stimulation regimes and laboratory protocols are also often established internationally without adequate validation. More recently, novel equipment that needs to be validated before it enters routine clinical use is being developed for IVF. With technologies such as producing gametes from stem cells around the corner, it is vital to ensure that the necessary research and development is conducted before bringing new techniques into clinical practice. Ideally, this should include preliminary work on animal models, such as mice/rats/rabbits/larger mammals, followed by studies on human embryos donated for research and finally well-designed RCTs with a follow up of all children born from the procedure. If such preliminary studies are not performed and published, it is possible that technology bringing no clinical benefit or leading to adverse health outcomes in the children born by these practices may be introduced. All IVF clinics need to consider the safety and efficacy of new technologies before introducing them.

Evaluation of the safety and effectiveness of intradermal administration of QR678 Neo® hair growth factor formulation: A phase-IV, open-label, single-arm multi-ethnicity clinical trial.

BACKGROUND: Intradermal administration of QR678 Neo® hair re-growth factor formulation has already proven its effectiveness and safety in treating androgenetic alopecia and female pattern hair loss. AIM: This study aims to evaluate effectiveness and safety of hair re-growth factor formulation at multiple centers for reduction of hair fall and regrowth of hair in androgenetic alopecia and female pattern hair loss. MATERIALS AND METHODS: An open-label, prospective, and interventional study was carried out at multiple centers of different countries. A total of 2428 patients with androgenetic alopecia and female pattern hair loss within the age range of 18-65 years were included in the study. Hair pull test, global photographic assessment, videomicroscopic assessment tests were performed at the beginning, after fourth and eighth sessions, and self-assessment through questionnaire related to satisfaction and side effects was carried out at beginning and at after eight session. RESULTS: Hair pull test was positive in only 12% of the patients after eight sessions. Beneficial results were noted in the global assessment score (mean-6) after fourth session and eighth session (mean-8). Huge improvement was noted in terminal hair count, vellus hair count, and hair density after eighth sessions. Also, with self-assessment score, a higher satisfaction score was noted. On long-term follow-up as well, no side effects were noted. CONCLUSION: Intradermal administration of QR678 Neo® is an innovative, efficacious, and safe technique for the treatment of androgenetic alopecia and female pattern hair loss.

Acute injection of ASP in the third ventricle inhibits food intake and locomotor activity in rats.

Acylation-stimulating protein (ASP; also known as C3adesArg) stimulates triglyceride synthesis and glucose transport via interaction with its receptor C5L2, which is expressed peripherally (adipose tissue, muscle) and centrally. Previous studies have shown that ASP-deficient mice (C3KO) and C5L2-deficient mice (C5L2KO) are hyperphagic (59 to 229% increase, P < 0.0001), which is counterbalanced by increased energy expenditure measured as oxygen consumption (Vo(2)) and a lower RQ. The aim of the present study was to evaluate ASP's effect on food intake, energy expenditure, and neuropeptide expression. Male rats were surgically implanted with intracerebroventricular (icv) cannulas directed toward the third ventricle. After a 5-h fast, rats were injected, and food intake was assessed at 0.5, 1, 2, 4, 16, 24, and 48 h, with a 5- to 7-day washout period between each injection. Acute icv injections of ASP (0.3-1,065 pmol) had a time-dependent effect on decreasing food intake by 20 to 57% (P < 0.05). Decreases were detected by 30 min (maximum 57%, P < 0.01) and at the highest dose effects extended to 48 h (19%, P < 0.05, 24- to 48-h period). Daily body weight gain was decreased by 131% over the first 24 h and 29% over the second 24 h (P < 0.05). A conditioned taste aversion test indicated that there was no malaise. Furthermore, acute ASP injection affected energy substrate usage, demonstrated by decreased Vo(2) and RQ (P < 0.05; implicating greater fatty acid usage), with a 49% decrease in total activity over 24 h (P < 0.05). ASP administration also increased anorexic neuropeptide POMC expression (44%) in the arcuate nucleus, with no change in NPY. Altogether ASP may have central in addition to peripheral effects.

Heparan sulfate-based treatments for regenerative medicine.

This review summarizes the emerging strategies that exploit the glycosaminoglycan sugar, heparan sulfate (HS), either as a substitute for, or as a supplement to growth factor (GF) therapy for regenerative medicine. Excluding autograft, the administration of GFs is currently the most effective treatment for critical bone repair and restoration. However, major hurdles in the clinical development of GF therapies include the high cost, the unwanted side effects, and the toxicity associated with the physiological overdosing required to achieve a successful outcome. These drawbacks may be overcome with the application of particular HS fractions that have been optimized to bind, recruit and enhance the biological activity of endogenous GF at the site of injury. Three HS-based treatments are discussed here: first, the single, localized, and sustained delivery of HS as a stand-alone therapeutic agent; then, the inclusion of an HS component within a delivery device so as to stabilize and potentiate the bioactivity of the incorporated GF; and finally, the growing use of HS mimetics, particularly for bone repair.