Prenatally engineered autologous amniotic fluid stem cell-based heart valves in the fetal circulation

Prenatal heart valve interventions aiming at the early and systematic correction of congenital cardiac malformations represent a promising treatment option in maternal-fetal care. However, definite fetal valve replacements require growing implants adaptive to fetal and postnatal development. The presented study investigates the fetal implantation of prenatally engineered living autologous cell-based heart valves. Autologous amniotic fluid cells (AFCs) were isolated from pregnant sheep between 122 and 128 days of gestation via transuterine sonographic sampling. Stented trileaflet heart valves were fabricated from biodegradable PGA-P4HB composite matrices (n = 9) and seeded with AFCs in vitro. Within the same intervention, tissue engineered heart valves (TEHVs) and unseeded controls were implanted orthotopically into the pulmonary position using an in-utero closed-heart hybrid approach. The transapical valve deployments were successful in all animals with acute survival of 77.8% of fetuses. TEHV in-vivo functionality was assessed using echocardiography as well as angiography. Fetuses were harvested up to 1 week after implantation representing a birth-relevant gestational age. TEHVs showed in vivo functionality with intact valvular integrity and absence of thrombus formation. The presented approach may serve as an experimental basis for future human prenatal cardiac interventions using fully biodegradable autologous cell-based living materials.     

The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism

IntroductionAndrogens are able to induce the development of secondary sexual characteristics in male patients suffering from hypogonadism. So far, the most common method of administering testosterone to induce puberty in these patients has been via the injection of testosterone ester formulations. Moreover, some evidence has showed that the length of polymorphism Cytosine‐Adenine‐Guanine (CAG) trinucleotide repeats present in androgen receptor (AR) gene might co‐regulate the effectiveness of testosterone therapy.AimThe aim of this study is to evaluate the effectiveness of a long‐acting injectable testosterone undecanoate (TU) formulation for the induction of secondary sexual characteristics in young males with hypogonadotropic hypogonadism (HH).Main Outcome MeasuresWe studied the different stages of puberty development that occur progressively according to the continuous increase in serum testosterone levels and, secondly, whether these changes might be modulated by the length of CAG repeats.MethodsNine male subjects over the age of 17 that had not undergone pubertal development because of HH were enrolled in this study and compared with 15 control males. Of these patients, 6/9 suffered from idiopathic HH and 3/9 experienced hypogonadism related to β‐thalassemia (BT). All patients underwent a clinical examination and a determination of follicle‐stimulating hormone, luteinizing hormone, sex hormone binding globulin (SHBG), and total testosterone (T) serum levels; the free fraction (FT) and biologically active fraction of testosterone were also determined. The number of CAG triplets present in the AR gene was obtained for each patient. For treatment, HH patients received an oral TU (Andriol, 120 mg/day) for 3 months, followed by intramuscular injection of parenteral TU (Nebid, 1,000 mg) every 14 weeks for 1 year, then every 12 weeks for a second year. Serum T and SHBG levels were assayed 3 months after the start of oral TU treatment and also in the 10th week following the start of the second round of intramuscular TU injections (e.g., the eighth month). Levels were also determined 12, 18, and 24 months after the start of the parenteral TU treatments.ResultsSerum levels of T, SHBG, FT, and BT increased in all of the patients receiving oral TU and parental TU treatments, and this was accompanied by a development of secondary sexual characteristics. For treated patients with >24 CAG triples vs. the HH subjects with ≤24 CAG triplets, a slight delay in the appearance of the most advanced phases of puberty and a slightly reduced final penis length were observed, suggesting that AR CAG polymorphism might co‐regulate the effectiveness of T treatment.ConclusionsLong‐acting parental TU was able to induce the puberty in our group of HH patients, even though additional studies are needed to elucidate the possible role of CAG repeats' length for the development of secondary sexual characteristics in young men with HH. Giagulli VA, Triggiani V, Carbone MD, Corona G, Tafaro E, Licchelli B, and Guastamacchia E. The role of long‐acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. J Sex Med **;**:**–**.     

Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain

Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimer's disease (AD) and non-demented controls. The -174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the -174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the -174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the -174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine.     

Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis

Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.     

Association of a wide invasive malignant thymoma with myastenia gravis and primary hyperparathyroidism due to parathyroid adenoma: case report and review of the literature

There are few cases described in the world literature reporting an association of thymoma (with myasthenia gravis or not) with hyperparathyroidism. In these cases the hyperparathyroidism was due to the presence of an adenoma or hyperplasic parathyroid tissue either in the cervical region or in an ectopic intrathymic location.(1-51, 5) In other cases the syndrome of hypercalcemia was due to the secretion of parathyroid-related protein (PTHRP) (6) or parathyroid hormone (PTH) (7) by the thymoma itself. We report the first case, at the best of our knowledge, of a wide invasive malignant thymoma (type B3), associated with myasthenia gravis and hyperparathyroidism caused by parathyroid adenoma.