Operative bleeding during thoracoscopic thymectomy: Causes and management strategies.

Bleeding during thoracoscopic thymectomy is a potentially critical complication that necessitates either immediate effective thoracoscopic control or conversion to an open approach. It can be difficult to manage and the surgeon must respond quickly in order to keep the patient safe . In this video tutorial we present various forms of intraoperative bleeding that can occur during thoracoscopic thymectomy and discuss how to manage them in patients with myasthenia gravis. Our management techniques include compression, clipping, stitching, and safe conversion to an open approach.

Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development.

The stromal microenvironment in the thymus is essential for generating a functional T cell repertoire. Thymic epithelial cells (TECs) are numerically and phenotypically one of the most prominent stromal cell types in the thymus, and have been recognized as one of most unusual cell types in the body by virtue of their unique functions in the course of the positive and negative selection of developing T cells. In addition to TECs, there are other stromal cell types of mesenchymal origin, such as fibroblasts and endothelial cells. These mesenchymal stromal cells are not only components of the parenchymal and vascular architecture, but also have a pivotal role in controlling TEC development, although their functions have been less extensively explored than TECs. Here, we review both the historical studies on and recent advances in our understanding of the contribution of such non-TEC stromal cells to thymic organogenesis and T cell development. In particular, we highlight the recently discovered functional effect of thymic fibroblasts on T cell repertoire selection.

Follistatin impacts Tumor Angiogenesis and Outcome in Thymic Epithelial Tumors.

Tumor angiogenesis is a key factor in the progression of thymic epithelial tumors (TETs). Activin A, a member of the TGFß family, and its antagonist Follistatin are involved in several human malignancies and angiogenesis. We investigated Activin A and Follistatin in serum and tumor tissue of patients with TETs in relation to microvessel density (MVD), WHO histology classification, tumor stage and outcome. Membranous Activin A expression was detected in all tumor tissues of TETs, while Follistatin staining was found in tumor nuclei and cytoplasm. Patients with TETs presented with significantly higher Activin A and Follistatin serum concentrations compared to healthy volunteers, respectively. Follistatin serum concentrations correlated significantly with tumor stage and decreased to physiologic values after complete tumor resection. Follistatin serum concentrations correlated further with MVD and were associated with significantly worse freedom from recurrence (FFR). Low numbers of immature tumor vessels represented even an independent worse prognostic factor for FFR at multivariable analysis. To conclude, the Activin A - Follistatin axis is involved in the pathogenesis of TETs. Further study of Follistatin and Activin A in TETs is warranted as the molecules may serve as targets to inhibit tumor angiogenesis and tumor progression.

Análise evolutiva da morfologia e da irrigação do timo de javalis (Sus scrofa Linnaeus, 1758) / Evolutionary analysis of morphology and irrigation of the thymus of boar's (Sus scrofa Linnaeus, 1758)

Objetivou-se descrever comparativamente as artérias responsáveis pela irrigação dos lobos tímicos cervicais e torácicos dos javalis, determinando-se também as características morfológicas do referido órgão nessa espécie, a ponto de correlacioná-las evolutivamente com os demais representantes da família Suidae. Os lobos tímicos cervicais direito e esquerdo receberam ramos distribuídos pelas artérias carótidas comuns direita e esquerda e cervicais superficiais direita e esquerda e, por vezes, pelas artérias torácica externa esquerda e subclávia esquerda. Essa característica vascular foi mantida ao longo da evolução, estando presente em linhagens e raças mais recentes de suídeos. A irrigação dos lobos tímicos torácicos direito e esquerdo foi realizada predominantemente por ramos diretos e indiretos ipsilaterais e contralaterais das artérias torácicas internas direita e esquerda, e também por ramos da artéria subclávia esquerda. Ramos diretos das artérias cervicais superficiais direita e esquerda e ramos diretos da artéria torácica interna direita foram encontrados para o lobo tímico médio, sendo essa uma descrição única nessa espécie, o que demonstra uma característica evolutiva primitiva nesse ancestral.(AU)

The objective of this study was to comparatively describe the arteries responsible for the irrigation of the cervical and thoracic thymus lobes of Boars, also determining the morphological characteristics of this body in this species to the point of evolutionarily correlating them with other representatives of the Suidae family. The left and right cervical thymic lobes received branches distributed by common right and left, superficial right and left carotid arteries, and neck and, sometimes, the outer left chest and left subclavian arteries. This feature was vascular maintained throughout evolution and is present in more recent strains and breeds of swine. Irrigation of the right and left thoracic thymic lobes was performed predominantly by direct and indirect ipsilateral and contralateral branches of the right and left internal thoracic arteries and also by branches of the left subclavian artery. Direct branches of the right and left superficial cervical artery and right branches of the right internal thoracic artery were found for the average thymic lobe, this being a unique description in this species, demonstrating a primitive feature in this evolutionary ancestor.(AU)

Late-Onset Vitamin K Deficiency Presenting as Scrotal Bruising and Mediastinal Mass.

Although there are several reports of intracranial hemorrhage associated with vitamin K deficient bleeding, there are few reported cases of extracranial manifestations, specifically involving the thymus. Here, we discuss the unique case of a 4-week-old infant presenting with scrotal discoloration, respiratory distress, and widened mediastinum, found to have thymic hemorrhage related to confirmed coagulopathy secondary to late-onset vitamin K deficiency bleeding of the newborn.

Differential requirement of kindlin-3 for T cell progenitor homing to the non-vascularized and vascularized thymus.

The role of integrin-mediated adhesion during T cell progenitor homing to and differentiation within the thymus is ill-defined, mainly due to functional overlap. To circumvent compensation, we disrupted the hematopoietic integrin regulator kindlin-3 in mice and found a progressive thymus atrophy that is primarily caused by an impaired homing capacity of T cell progenitors to the vascularized thymus. Notably, the low shear flow conditions in the vascular system at midgestation allow kindlin-3-deficient fetal liver-derived T cell progenitors to extravasate via pharyngeal vessels and colonize the avascular thymus primordium. Once in the thymus, kindlin-3 promotes intrathymic T cell proliferation by facilitating the integrin-dependent crosstalk with thymic antigen presenting cells, while intrathymic T cell migration, maturation into single positive CD4 and CD8 T cells and release into the circulation proceed without kindlin-3. Thus, kindlin-3 is dispensable for integrin-mediated T cell progenitor adhesion and signalling at low and indispensable at high shear forces.

Thymus involvement in early-onset myasthenia gravis.

It has long been established that the thymus plays a central role in autoimmune myasthenia gravis (MG) because of either thymoma or thymic hyperplasia of lymphoproliferative origin. In this review, we discuss thymic changes associated with thymic hyperplasia and their implications in the development of an autoimmune response against the acetylcholine receptor (AChR).The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development. As thymic epithelial cells or myoid cells express AChR, a specific antigen presentation can easily occur within the thymus in the presence of recruited peripheral cells, such as B cells and T follicular helper cells. How the thymus turns into a TLO is not known, but local inflammation seems mandatory. Interferon (IFN)-ß is overexpressed in MG thymus and could orchestrate thymic changes associated with MG. Knowledge about how IFN-ß is induced in MG thymus and why its expression is sustained even long after disease onset would be of interest in the future to better understand the etiological and physiopathological mechanisms involved in autoimmune MG.

A rare arterial branch distributing to the thymus, ectopic intrathymic parathyroid, and thyroid glands which passed ventral to the right common carotid artery: a case report.

The intrathymic parathyroid has been reported that this variation might be related with the hyperthyroidism. In this study, the arterial pattern supplying the intrathymic parathyroid was examined in detail in the human cadaver (67-year-old, female, right side). The ectopic parathyroid was only detected on the right side, but not on the left side. This ectopic intrathymic parathyroid was supplied by the supernumerary arterial branch that originated from the inferior thyroid artery and passed ventral to the common carotid artery. This supernumerary branch further divided into two thin branches: (1) the one distributing the intrathymic parathyroid and the right lobe of the thyroid gland and (2) the other descending toward the thoracic cavity to supply the mediastinum organs. Other arteries supplying the thyroid gland and thymus of both sides were normal. In the surgical resection of the ectopic intrathymic parathyroid, physicians should pay attention to arteries ventral to the common carotid artery. This supernumerary branch distributing to the intrathymic parathyroid may be caused by incomplete division into the primordium for the inferior parathyroid and the primordium for the thymus on the developmental process.

Gender-related Histological Changes in the Thymus Gland After Pinealectomy and Short-term Melatonin Treatment in Rats.

OBJECTIVES: The aim of this study was to investigate the effects of pinealectomy and melatonin treatment on the rat thymus gland characteristics, taking into consideration possible gender differences. MATERIALS AND METHODS: Thirty adult Wistar rats of both sexes were divided into three groups. Group C and group PX served as control groups and included sham-pinealectomized and pinealectomized animals that were treated with 10% ethanol solution (0,1ml/daily, subcutaneous). Animals from third group (group PXM) underwent pinealectomy and seven days after surgery started receiving melatonin dissolved in 10% ethanol solution (3mg/kg/daily, subcutaneous). All animals were treated for 4 weeks. RESULTS: Volume density of the thymus cortex showed statistically significant (p<0,05) decrease while the volume density of the thymus medulla was increased in the pinealectomized compared to the sham-pinealectomized female rats. Numerical density of macrophages as well as the distribution of blood vessels showed no gender differences. The numerical density of lymphocytes was statistically significantly decreased in female in comparison to the male pinealectomized rats. Melatonin treatment was proved to cause reverse effects in the sense that the results from the melatonin treated group corresponded to the results obtained from the control group of animals. CONCLUSION: The results of this study suggest that the pinealectomy causes gender-related changes in the rat thymus. Short-term melatonin treatment showed reverse effect, equally in both sexes.

[MORPHO-FUNCTIONAL CHANGES OF THYMUS TISSUES IN CHILDREN WITH CONGENITAL HEART DISEASE].

Biopsy specimens of the thymus were studied in children aged under 11 months (n = 77) with congenital heart defects and circulatory hypoxia of varying severity. Histological sections were stained with hematoxylin-eosin and Shubich's method (to demonstrate mast cells). The expression of Ki-67, CD3 and CD34 was assessed by immunohistochemistry. The ultrastructure of thymic tissues was also examined. It was found that the severity of hypoxia determined the morphological changes in the organ associated with a development of large complex of tissue reactions. A disruption of internal structure and a loss of integrity of epithelio-reticular cells and thymocytes were demonstrated in ultrathin sections. Thymocyte proliferation index (Ki-67) and thymocytopoiesis intensity (CD3+) were reduced in all the zones of the thymus. The degree of hypoxia affected the redistribution of CD3+ lymphocytes leading to their accumulation in the medulla. The processes of endogenous regeneration took place which involved the cells of fibroblastic line and progenitor cells (CD34+) together with active formation of new blood vessels. These findings suggest that the morphological changes identified in the tissues of the thymus are a manifestation of tissue adaptation to hypoxia of varying severity under conditions of endogenous regeneration, simultaneously reflecting the processes of substitution cytogenesis.

Comparative anatomical studies on the thyroid and thymic arteries. VI. Diprotodont marsupials.

The thyroid and thymic arteries in 44 specimens from 18 species belonging to the diprotodont marsupials were investigated. The results were compared with those of polyprotodont marsupials, suncuses, rats, rabbits, guinea pigs, and man. The superior thyroid artery was constant in three superfamily groups. The inferior thyroid artery was extremely rare. The superior thymic artery arising from the thyrocervical trunk was observed in 1 phalangeroid and 2 macropodoids, and that arising from the vertebral artery occurred in 1 macropodoid. The middle thymic artery occurred in 1 phalangeroid, but was abundant in macropodoids. The inferior thymic artery was constant in koalas and phalangeroids, but was absent in half of the macropodoids. The thyroid ima, middle thymothyroid, and the supreme thymic arteries were absent in all diprotodonts. In addition to the usual thymus, diprotodonts have the superficial cervical thymus, which is only shared with guinea pigs. The superior superficial cervical thymic artery was absent in koalas and in half of the macropodoids, but was abundant in the phalangeroids. Conversely, the inferior superficial cervical thymic artery was constant in koalas and was dominant in the macropodoids. These results show that variations in the arterial patterns for both organs were much more prevalent in macropodoids than in phalangeroids, while the arterial patterns in koalas were characteristic. As a whole, the arteries for both organs were more complex in diprotodonts than in polyprotodonts or rats, but more simple than those in rabbits or man. The superior superficial cervical thymic arteries, which showed various patterns, were compared with those in guinea pigs.

Massive thymic hemorrhage and hemothorax occurring in utero.

BACKGROUND: Thymic enlargement is a common and physiological finding in children and neonates' X-rays, but it is usually asymptomatic. Occasionally it can cause respiratory distress. In most cases the aetiology of this expansion remains unclear and it is diagnosed as a thymic hyperplasia. True thymic hyperplasia is defined as a gland expansion, both in size and weight, while maintaining normal microscopic architecture. Often it is a diagnosis of exclusion and prognosis is good. Thymic haemorrhage is an unusual condition related to high foetal and neonatal mortality. CASE PRESENTATION: We report a case of spontaneous massive thymic haemorrhage in a newborn developing at birth acute respiratory distress associated with severe bilateral haemothorax. Thymic enlargement was evident after pleural evacuation and confirmed by radiographic, Computed Tomography (CT) images and Magnetic Resonance Imaging (MRI) sequences. The spontaneous resolution of this enlargement seen with CT scan and MRI sequences suggested a thymic haemorrhage; surgery was not necessary. CONCLUSION: Thymic haemorrhage should be considered in newborn infants with pleural effusion, mediastinal space enlargement and Respiratory Distress.

The discovery of the blood-thymus barrier.

The blood-thymus barrier is a functional and selective barrier separating T-lymphocytes from blood and cortical capillaries in the cortex of the thymus. The existence of this barrier was proposed for the first in time in 1961 by Marshall and White, and demonstrated in 1963 by Clark and Weiss. The most clear morphological evidence concerning the existence of the blood-thymus barrier may be attributed to the collaborative work published in 1972 by two scientists, Morris Karnovsky and Elio Raviola. Raviola and Karnovsky, using peroxidase as a permeability tracer, demonstrated that the venules at the cortico-medullary junction are the site of leakage for blood antigens, while the capillaries draining the cortex are largely impermeable. Other permeability studies have confirmed the existence of a blood-thymus barrier, which allow the access to low molecular weight tracers, while most exclude high molecular weight particles.

Fibronectin signals through integrin α5ß1 to regulate cardiovascular development in a cell type-specific manner.

Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in the pharyngeal region may be essential for cardiovascular morphogenesis. To test this hypothesis, we ablated Fn1 using the Isl1(Cre) knock-in strain of mice. Deletion of Fn1 using the Isl1(Cre) strain resulted in defective formation of the 4th pharyngeal arch arteries (PAAs), aberrant development of the cardiac outflow tract (OFT), and ventricular septum defects. To determine the cell types responding to Fn1 signaling during cardiovascular development, we deleted a major Fn1 receptor, integrin α5 using the Isl1(Cre) strain, and observed the same spectrum of abnormalities seen in the Fn1 conditional mutants. Additional conditional mutagenesis studies designed to ablate integrin α5 in distinct cell types within the Isl1(+) tissues and their derivatives, suggested that the expression of integrin α5 in the pharyngeal arch mesoderm, endothelium, surface ectoderm and the neural crest were not required for PAA formation. Our studies suggest that an (as yet unknown) integrin α5-dependent signal extrinsic to the pharyngeal endothelium mediates the formation of the 4th PAAs.

Effect of Hypoxic Preconditioning on Stress Reaction in Rats.

In rats, immobilization stress (24 h) induced involution of the thymus and spleen, adrenal hypertrophy, and pronounced elevation (by 67%) of serum cortisol in comparison with intact animals; the mean number of stomach ulcers in rats subjected to stress was 6.9. Hypoxic preconditioning consisting of 6 sessions of 10-min hypoxia (8% O2) followed by 10-min reoxygenation with atmospheric air induced adrenal hypertrophy and spleen involution, but did not change blood cortisol level; no stomach ulcers were found in preconditioned rats. In rats subjected to both hypoxic preconditioning and immobilization, the weights of the thymus, adrenal glands, and spleen, as well as cortisol level did not differ from the corresponding parameters in rats subjected to immobilization stress alone. The number of stomach ulcers in experimental rats was 1.5-fold lower than in the stress-control ones. Thus, hypoxic preconditioning exerts a pronounced preventive anti-ulcer effect during immobilization, but it does not affect other indices of the stress reaction.

Effects of hypoxia and its relationship with apoptosis, stem cells, and angiogenesis on the thymus of children with congenital heart defects: a morphological and immunohistochemical study.

INTRODUCTION: The thymus slowly involutes with age after puberty. Various stress conditions accelerate the involution of the thymus and cause changes in the histologic structure of the gland. OBJECTIVE: The present study performed histomorphological and immunohistochemical (IHC) evaluations of the thymus glands removed during surgical repair in patients with cyanotic or acyanotic congenital heart disease (CHD). The thymus glands in the hypoxic group were compared to those in the non-hypoxic group. This study suggested that the activation of HIF-1 alpha promotes tumor progression and impair prognosis due to the inhibition of apoptosis, increased population of stem cells, and induction of angiogenesis also suggested that inactivation of HIF-1 alpha in tumor-infiltrated tissues could halt tumor progression and improve prognosis. MATERIALS AND METHODS: The study included 76 thymus glands removed from patients who underwent an operation due to CHD. Of these cases, 38 had cyanotic CHD, and constituted the hypoxic group. The remaining 38 patients had acyanotic CHD, and constituted the non-hypoxic group. IHC procedures were performed for HIF-1 alpha, FoxP3, CD44, Bcl-2, and CD34. RESULTS: There were statistically significant differences between the hypoxic and non-hypoxic groups only in terms of medullary enlargement toward the cortex and effacement of the corticomedullary junction. In the immunohistochemical examination for five markers, staining intensity and staining rates increased with decreasing oxygen saturation. CONCLUSION: It can be concluded that the activation of HIF-1 alpha promotes tumor progression and impair prognosis due to the inhibition of apoptosis, increased population of stem cells, and induction of angiogenesis.

EMF radiation at 2450 MHz triggers changes in the morphology and expression of heat shock proteins and glucocorticoid receptors in rat thymus.

AIMS: Electromagnetic fields (EMFs) can act as inducers or mediators of stress response through the production of heat shock proteins (HSPs) that modulate immune response and thymus functions. In this study, we analyzed cellular stress levels in rat thymus after exposure of the rats to a 2.45 GHz radio frequency (RF) using an experimental diathermic model in a Gigahertz Transverse Electromagnetic (GTEM) chamber. MAIN METHODS: In this experiment, we used H&E staining, the ELISA test and immunohistochemistry to examine Hsp70 and Hsp90 expression in the thymus and glucocorticoid receptors (GR) of 64 female Sprague­Dawley rats exposed individually to 2.45 GHz (at 0, 1.5, 3.0 or 12.0 W power). The 1 g averaged peak and mean SAR values in the thymus and whole body of each rat to ensure that sub-thermal levels of radiation were being reached. KEY FINDINGS: The thymus tissue presented several morphological changes, including increased distribution of blood vessels along with the appearance of red blood cells and hemorrhagic reticuloepithelial cells. Levels of Hsp90 decreased in the thymus when animals were exposed to the highest power level (12 W), but only one group did not show recovery after 24 h. Hsp70 presented no significant modifications in any of the groups. The glucocorticoid receptors presented greater immunomarking on the thymic cortex in exposed animals. SIGNIFICANCE: Our results indicate that non-ionizing sub-thermal radiation causes changes in the endothelial permeability and vascularization of the thymus, and is a tissue-modulating agent for Hsp90 and GR.

Premature thymic involution is independent of structural plasticity of the thymic stroma.

The thymus is the organ devoted to T-cell production. The thymus undergoes multiple rounds of atrophy and redevelopment before degenerating with age in a process known as involution. This process is poorly understood, despite the influence the phenomenon has on peripheral T-cell numbers. Here we have investigated the FVB/N mouse strain, which displays premature thymic involution. We find multiple architectural and cellular features that precede thymic involution, including disruption of the epithelial-endothelial relationship and a progressive loss of pro-T cells. The architectural features, reminiscent of the human thymus, are intrinsic to the nonhematopoietic compartment and are neither necessary nor sufficient for thymic involution. By contrast, the loss of pro-T cells is intrinsic to the hematopoietic compartment, and is sufficient to drive premature involution. These results identify pro-T-cell loss as the main driver of premature thymic involution, and highlight the plasticity of the thymic stroma, capable of maintaining function across diverse interstrain architectures.

Thymic artery: uncommon origin from proximal aortic arch or distal ascending aorta.

Internal thoracic and inferior thyroid arteries mainly supply the thymus. However, very few studies have been reported on the arterial variations of the thymus. The first author, a cardiac surgeon, happened upon a thymic artery arising from either proximal aortic arch or distal ascending aorta in a few cases during routine cardiac surgery in infants and neonates. Hence a study on the prevalence of the variant thymic artery during open heart surgery was contemplated, as knowledge of its presence could avoid its injury during surgical and diagnostic procedures of the region. The prevalence of the variant thymic artery was observed during 100 consecutive cardiac surgeries in infants and neonates. In addition to two branches from internal thoracic and inferior thyroid arteries, a thymic artery originating from the distal ascending aorta or proximal arch was found in 15 (15%) out of 100 patients who underwent open heart surgery for the correction of congenital heart defects. The artery took origin from the anterior surface of aorta, a little to the left. These were small arteries, single in origin, which started at right angles from the aorta and pierced the pericardium at its reflection, from visceral to parietal, to reach the posterior surface of the thymus where they divided into two branches, one for each lobe. Since this variant artery was present in 15% cases, being aware of its presence can help prevent troublesome bleeding during surgical thymectomy, and more importantly, during surgical and diagnostic interventions in the mediastinum.