Development of Hip Bone Geometry During Gender-Affirming Hormone Therapy in Transgender Adolescents Resembles That of the Experienced Gender When Pubertal Suspension Is Started in Early Puberty

Bone geometry can be described in terms of periosteal and endocortical growth and is partly determined by sex steroids. Periosteal and endocortical apposition are thought to be regulated by testosterone and estrogen, respectively. Gender-affirming hormone (GAH) treatment with sex steroids in transgender people might affect bone geometry. However, in adult transgender people, no change in bone geometry during GAH was observed. In this study, we investigated changes in bone geometry among transgender adolescents using a gonadotropin-releasing hormone agonist (GnRHa) and GAH before achieving peak bone mass. Transgender adolescents treated with GnRHa and subsequent GAH before the age of 18 years were eligible for inclusion. Participants were grouped based on their Tanner stage at the start of GnRHa treatment and divided into early, mid, and late puberty groups. Hip structure analysis software calculating subperiosteal width (SPW) and endocortical diameter (ED) was applied to dual-energy X-ray absorptiometry scans performed at the start of GnRHa and GAH treatments, and after ≥2 years of GAH treatment. Mixed-model analyses were performed to study differences over time. Data were visually compared with reference values of the general population. A total of 322 participants were included, of whom 106 were trans women and 216 trans men. In both trans women and trans men, participants resembled the reference curve for SPW and ED of the experienced gender but only when GnRHa was started during early puberty. Those who started during mid and late puberty remained within the reference curve of the gender assigned at birth. A possible explanation might be sought in the phenomenon of programming, which conceptualizes that stimuli during critical windows of development can have major consequences throughout one's life span. Therefore, this study adds insights into sex-specific bone geometry development during puberty of transgender adolescents treated with GnRHa, as well as the general population. © 2021 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

A novel controlled drug-delivery system for growth hormone applied to healing skin wounds in diabetic rats

Controlled release systems for drugs, hormones and growth factors can be particularly useful in tissue repair processes. These systems act as a biodegradable support containing the substance to be delivered, allowing their gradual release. In the past years, the local application of growth factors has acquired special relevance as a therapeutic option for use in subjects who show deficient tissue scarring, the hormone dose being the limiting factor for its success. In this study, the in vitro biocompatibility of a copolymer formed by vinylpyrrolidone and 2-hydroxyethyl methacrylate, used as an administration vehicle for hGH, was evaluated. The system was then tested in vivo in terms of its capacity for healing incisional wounds in healthy and diabetic rats. For the in vitro studies, polymer and hormone degradation rates were determined, and polymer biocompatibility was evaluated in fibroblast cultures. In the in vivo experiments, an incision was made in the back of the animals, and polymers discs with/without hGH, were introduced in the aperture. Morphological, immunohistochemical and morphometric evaluations were performed on wound tissue specimens 3-10 days after surgery. In vitro, the polymer was found to be biodegradable and showed no toxic effects on fibroblasts, the hormone being slowly released to the culture medium. In untreated diabetic rats, a delayed skin scarring and cell response were observed, compared to that noted in healthy animals. Skin closure, keratinisation and fibrosis occurred earlier in the presence of the polymer-hGH system. The use of this co-polymer as an administration vehicle for hGH improves the wound scarring process in the pathological setting of diabetes.     

Bioactive functionalized polymer of malic acid for bone repair and muscle regeneration

A bioactive poly(β-hydroxyalkanoate) derived from malic acid was prepared and tested on bone repair and muscle regeneration. This functionalized and hydrolyzable polymer was obtained after several steps, the first one being the anionic copolymerization of three malolactonic acid esters. Chemical modifications were carried out on the terpolymer to turn benzyl-protecting groups into carboxyl groups and allyl groups into sulfonate groups. The resulting polymer bore carboxylate, sulfonate, and sec-butyl pendent groups in 65/25/10 molar proportions and were aimed at interacting with heparan binding growth factors. This polymer did not present any toxic effect in cell viability of HepG₂ cells, over a large range of concentrations (0.01-0.25 mg l^-1). Its ability to improve wound healing was tested in vivo and positive results are reported. Furthermore, the bioactivity of this polymer was evaluated using the regeneration model of Extensor digitorum longus (EDL) rat muscle. The study displayed a significant increase in the muscle regeneration and maturation.     

Prevalence and Incidence of Hypoparathyroidism in the United States Using a Large Claims Database

Hypoparathyroidism is a rare endocrine disorder whose incidence and prevalence have not been well defined. This study aimed to 1) estimate the number of insured adult patients with hypoparathyroidism in the United States and 2) obtain physician assessment of disease severity and chronicity. Prevalence was estimated through calculation of diagnoses of hypoparathyroidism in a large proprietary health plan claims database over a 12‐month period from October 2007 through September 2008 and projected to the US insured population. Incidence was also calculated from the same database by determining the proportion of total neck surgeries resulting in either transient (≤6 months) or chronic (>6 months) hypoparathyroidism. A physician primary market research study was conducted to assess disease severity and determine the percentage of new nonsurgical patients with hypoparathyroidism. Incidence data were entered into an epidemiologic model to derive an estimate of prevalence. The diagnosis‐based prevalence approach estimated 58,793 insured patients with chronic hypoparathyroidism in the United States. The surgical‐based incidence approach yielded 117,342 relevant surgeries resulting in 8901 cases over 12 months. Overall, 7.6% of surgeries resulted in hypoparathyroidism (75% transient, 25% chronic). The prevalence of chronic hypoparathyroidism among insured patients included in the surgical database was estimated to be 58,625. The physician survey found that 75% of cases treated over the past 12 months were reported due to surgery and, among all thyroidectomies and parathyroidectomies and neck dissections performed in a year, 26% resulted in transient hypoparathyroidism and 5% progressed to a chronic state. In conclusion, the two claims‐based methods yielded similar estimates of the number of insured patients with chronic hypoparathyroidism in the United States (～58,700). The physician survey was consistent with those calculations and confirmed the burden imposed by hypoparathyroidism. © 2013 American Society for Bone and Mineral Research.     

Tacrolimus (FK506) and cyclosporin A reduce macrophage recruitment to the rat brain injured at perinatal and early postnatal periods

Abstract

Objective: The present article presents an overview of the literature, and analyses the methods and the primary questions related to assessment of proliferation index using the Ki-67/MIB-1 labeling index in pituitary adenomas. Although atypical adenomas are characterized by their atypical morphological features by an elevated mitotic index, a Ki-67 (MIB-1) labeling index greater than 3% and extensive nuclear staining for p53, use of the proliferation index (LI) of pituitary adenomas in assessing the degree of tumor aggressiveness is a controversial topic in the literature, and there are disparate results involving many studies.

Methods: A review of literature was carried out to correlate the role of Ki-67 LI and its correlation with clinical findings, tumor size, invasiveness, recurrence, adenoma subtype, adenoma doubling time, and pituitary carcinomas is addressed.

Results: The prognosis cannot be predicted on the basis of the Ki-67 LI alone. Although there is no direct relation between Ki-67 LI and some of these variables and controversial data were found regarding some topics, our review justify the use of Ki-67 in the analysis of pituitary adenomas as an additional information for clinical decision.

Conclusion: Although assessment of proliferative may be helpful in predicting subsequent tumor recurrence or invasiveness, there are many other important and as yet unidentified factors pituitary tumors. It is clear that further research is needed to clarify these molecular mechanisms to predict those with a potentially poor clinical outcome.     

Surgical Correction of Patent Ductus Venosus in Three BroThers

We report the presence of a patent ductusvenosus in three brothers who underwent surgicalcorrection. Patent ductus venosus was demonstrated byultrasonography. Portosystemic venous shunt ratios asevaluated by [¹²³I]iodoamphetamine per rectalportal scintigraphy were 67%, 50%, and 77%,respectively. Histologic examination of liver biopsyspecimens revealed fatty degeneration in all cases.Portal vein pressure before and after temporarily occluding thepatent ductus venosus was estimated by an Anthron P-Ucatheter introduced into the portal vein via theligament teres hepatis. Portal venous pressure increased from 10 to 17 cm H₂O, 16 to 23 cmH₂O, and 14 to 27 cm H₂O,respectively. Therefore, banding of the ductus venosuswith Teflon tape was attempted to prevent portalhypertension following complete ligation. As a result, portal venous pressures afterstricture of the ductus venosus were 12, 21, and 20 cmH2), respectively. Bile acid and liver enzymes decreasedand returned to normal within 14 days after surgery. Interestingly, serum concentrations ofhepatocyte growth factor (HGF) increased significantlyafter restoration of the portal blood flow and thengradually decreased, but remained persistently elevated for at least two weeks in two cases measuredafter surgical correction. One month after correction,liver function returned to normal as assessed byserological and histological parameters in all cases. These results suggest that it is important todetermine whether stricture or complete ligation isindicated for a patent ductus venosus during surgicalcorrection, based on the portal venous pressure after temporal test occlusion of the duct. Inaddition, HGF may be a useful marker for normalizationof hepatic microcirculation after surgery.     

The Effect of Aligned Core–Shell Nanofibres Delivering NGF on the Promotion of Sciatic Nerve Regeneration

Recent bioengineering strategies for peripheral nerve regeneration have been focusing on the development of alternative treatments for nerve repair. In this study, we incorporated nerve growth factor (NGF) into aligned core–shell nanofibres by coaxial electrospinning, and reeled the scaffold into aligned fibrous nerve guidance conduits (NGCs) for nerve regeneration study. This aligned PLGA/NGF NGC combined physical guidance cues and biomolecular signals to closely mimic the native extracellular matrix (ECM). The effect of this aligned PLGA/NGF NGC on the promotion of nerve regeneration was evaluated in a 13-mm rat sciatic nerve defect using functional and morphological analysis. After 12 weeks implantation, the results of electrophysiological and muscle weight examination demonstrated that the functional recovery of the regenerated nerve in the PLGA/NGF NGC group was significantly better than that in the PLGA group, yet had no significant difference compared with the autograft group. The toluidine blue staining study showed that more nerve fibres were regenerated in the PLGA/NGF group, while the electron microscopy study indicated that the regenerated nerve in the PLGA/NGF group was more mature than that in the PLGA group. This study demonstrated that the aligned PLGA/NGF could greatly promote peripheral nerve regeneration and have a potential application in nerve regeneration.     

The Effects of One-Step Self-Etch Adhesives on the Induction of Oxidative Stress and Production of TGF-β1 and BMP-2 by Human Gingival Fibroblasts

The aim of this study was to evaluate and compare the effects of two self-etch adhesive materials on the induction of oxidative stress and production of transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) by cultured human gingival fibroblasts (HGF). Inflammation-free attached gingiva was obtained from healthy donors under informed consent. Following 24- and 72-h exposure of HGF to two different elutes of the test materials, cell viability was determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Lipid peroxidation, a major indicator of oxidative stress, was measured by the thiobarbituric acid reactive substance (TBARS) assay. TGF-β1 and BMP-2 levels in cell-free culture media were determined by enzyme-linked immunosorbent assay (ELISA). Cell viability of the test groups was significantly lower than those of control at 24 and 72 h (P < 0.001), but showed an increase at 72 h (P < 0.001). The TBARS levels of both test groups were significantly greater than that of control (P < 0.05), and displayed similar values at 72 h (P > 0.05). For both materials, the levels of TGF-β1 and BMP-2 were significantly greater than that of control (P < 0.05). Both test groups showed increased TGF-β1 levels. These results indicate that the tested self-etch adhesives might be capable of inducing production of TGF-β1 and BMP-2 in cultured HGF, despite their cytotoxic and oxidative stress-producing potential.     

Novel Degradable Co-polymers of Polypyrrole Support Cell Proliferation and Enhance Neurite Out-Growth with Electrical Stimulation

Synthetic polymers such as polypyrrole (PPy) are gaining significance in neural studies because of their conductive properties. We evaluated two novel biodegradable block co-polymers of PPy with poly(ε-caprolactone) (PCL) and poly(ethyl cyanoacrylate) (PECA) for nerve regeneration applications. PPy–PCL and PPy–PECA co-polymers can be processed from solvent-based colloidal dispersions and have essentially the same or greater conductivity (32 S/cm for PPy–PCL, 19 S/cm for PPy–PECA) compared to the PPy homo-polymer (22 S/cm). The PPy portions of the co-polymers permit electrical stimulation whereas the PCL or PECA blocks enable degradation by hydrolysis. For in vitro tests, films were prepared on polycarbonate sheets by air brushing layers of dispersions and pressing the films. We characterized the films for hydrolytic degradation, electrical conductivity, cell proliferation and neurite extension. The co-polymers were sufficient to carry out electrical stimulation of cells without the requirement of a metallic conductor underneath the co-polymer film. In vitro electrical stimulation of PPy–PCL significantly increased the number of PC12 cells bearing neurites compared to unstimulated PPy–PCL. For in vivo experiments, the PPy co-polymers were coated onto the inner walls of nerve guidance channels (NGCs) made of the commercially available non-conducting biodegradable polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB-HV). The NGCs were implanted in a 10 mm defect made in the sciatic nerve of rats, and harvested after 8 weeks. Histological staining showed axonal growth. The studies indicated that these new conducting degradable biomaterials have good biocompatibility and support proliferation and growth of PC12 cells in vitro (with and without electrical stimulation) and neurons in vivo (without electrical stimulation).     

Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project

The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow‐up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005–2007), 2 years follow‐up (2007–2009), and 5 years follow‐up (2010–2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography–tandem mass spectrometry (LC‐MS/MS), and sex hormone–binding globulin (SHBG), luteinizing hormone (LH), and follicle‐stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X‐ray absorptiometry (DXA) at all three time‐points. Fracture data were collected at 4‐monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (β = –0.071), FSH (β = –0.085), LH (β = –0.070), and E1 (β = 0.107) remained significantly associated with BMD loss in multivariate‐adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171; hip, n = 44; and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate‐adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate‐adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging. © 2015 American Society for Bone and Mineral Research.