Citations

AbstractOn May 27, 2022, the Asia Pacific Heart Rhythm Society and the Heart Rhythm Society convened a meeting of leaders from different professional societies of healthcare providers committed to arrhythmia care from the Asia Pacific region. The overriding goals of the meeting were to discuss clinical and health policy issues that face each country for providing care for patients with electrophysiologic issues, share experiences and best practices, and discuss potential future solutions. Participants were asked to address a series of questions in preparation for the meeting. The format of the meeting was a series of individual country reports presented by the leaders from each of the professional societies followed by open discussion. The recorded presentations from the Asia Summit can be accessed at https://www.heartrhythm365.org/URL/asiasummit‐22. Three major themes arose from the discussion. First, the major clinical problems faced by different countries vary. Although atrial fibrillation is common throughout the region, the most important issues also include more general issues such as hypertension, rheumatic heart disease, tobacco abuse, and management of potentially life‐threatening problems such as sudden cardiac arrest or profound bradycardia. Second, there is significant variability in the access to advanced arrhythmia care throughout the region because of differences in workforce availability, resources, drug availability, and national health policies. Third, collaboration in the area already occurs between individual countries, but no systematic regional method for working together is present.

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

Pituitary tumor transforming gene (PTTG) was initially found to be overexpressed in GH4 rat pituitary adenomas (PA). PTTG overexpression has been correlated with patient survival, tumor grade, and/or invasiveness in several tumors including those of thyroid, breast, lung, and colon. Studies of PTTG as a prognostic indicator in PAs are limited and show conflicting results. We investigated PTTG immunostaining in 79 PAs of different subtypes (growth hormone (GH), 12; prolactin (PRL), 6, adrenocorticotropic hormone (ACTH), 11, gonadotroph, 21; null cell, 29) in relation to clinico‐pathological variables including patient age and sex, as well as tumor size, and invasiveness. The streptavidin‐biotin‐peroxidase method was used, with a monoclonal PTTG antibody (Abcam, Cambridge, UK). PTTG expression was found to be cytoplasmic in all PAs, with highest levels being present in GH adenomas and lowest in the PRL ones. No correlation was found with patient age, sex, tumor size or invasiveness. Thus, it appears that PTTG cannot serve as a prognostic marker in patients with PAs. PTTG has been implicated in several tumorigenic processes including angiogenesis, DNA damage repair and invasiveness. PTTG overexpression in PA warrants further research into its role in PA initiation and progression.

Estrogen is involved in pituitary tumorigenesis, acting through estrogen receptors alpha (ERα) and beta (ERβ). Our study investigated the prognostic value of ERα/ERβ as markers in pituitary adenomas. Tissue samples and clinico‐pathological data (patient age and sex, tumor size, invasiveness and recurrence) were obtained from 78 patients with pituitary adenomas. Immunohistochemistry was performed using the streptavidin‐biotin‐peroxidase complex method. A monoclonal and polyclonal antibody were used for ERα and ERβ expression respectively. Intensity of ERα/ERβ expression was evaluated using a scale of 0 to 3. Percentage of positive cells was evaluated on a scale of 0 to 4. ERα immunopositivity was evident in 40 of 78 cases (51%), while ERβ stained positive in 49 of 78 cases (63%). No correlation was found between ERβ expression and pituitary tumor cell types or clinico‐pathological factors. A significant difference was present in ERα expression between different tumor types. ERα positivity was present to a greater extent in macroadenomas. This finding supports the role of ERα in tumor growth and progression. Elevated ERα positivity and intensity were also found in non‐invasive adenomas. It appears that ERα may be a valuable biological marker for tumor size and invasiveness, while ERβ is a poor marker. The role of ERα expression in pituitary tumor initiation and progression warrants further investigation.

Rab3B, is a low molecular weight GTP binding protein implicated in the regulation of exocytosis. To shed light on its presence in the pituitary, an immunohistochemical study of 130 surgically removed human pituitary adenomas was undertaken, including 23 somatotroph, 32 lactotroph, 19 functioning corticotroph, 10 silent subtype 1 and 8 silent subtype 2 corticotroph, 12 gonadotroph, 10 thyrotroph, 7 subtype 3, and 9 null cell adenomas. Ten lactotroph adenomas were pretreated with bromocriptine, a dopamine agonist and 10 somatotroph adenomas with octreotide, a somatostatin analog. Ten autopsy obtained nontumorous adenohypophyses were also examined. The tumors were classified on the basis of their histologic, immunohistochemical and ultrastructural characteristics. Rab3B immunopositivity was strongest in corticotrophs followed by thyrotroph, lactotroph, gonadotroph, Subtype 3, null cell and somatotroph adenomas. No difference was noted between endocrinologically active and silent corticotroph adenomas. Bromocriptine therapy was associated with decreased Rab3B immunoexpression, whereas pretreatment with octreotide induced no significant reduction. Immunopositivity was cytoplasmic and evenly distributed. No staining was noted in the nontumorous adenohypophyses. Our results add new information to the view that Rab3B is involved in the regulation of pituitary hormone secretion.

The aim of our work was to investigate immunohistochemical expression of nestin, a member of the intermediate filament family, in the adenohypophysial vasculature during the development and progression of pituitary infarction. Non‐tumorous adenohypopheses (45 cases) and pituitary adenomas (34 cases) of various types, all exhibiting acute or healing infarcts were examined. The streptavidin‐biotin‐peroxidase complex method was applied. In areas of adenohypophyses and pituitary adenomas with no infarction, nestin was expressed in scattered capillaries and endothelial cells. In acute infarcts, no nestin was demonstrable in the necrotic capillaries (50 cases). Where newly formed capillaries spread into necrotic zones, nestin expression was noted in all capillaries (25 cases). In the hypocellular, fibrotic scar phase, only few vessels were apparent and immunoreactivity was focal and mild (4 cases). In conclusion, nestin is strongly expressed in newly formed capillaries and is downregulated when infarcts transform to fibrous tissue. Nestin expression may provide valuable insight into the process of pituitary angiogenesis.

Pituitary tumor transforming gene (PTTG) plays a role in many cellular processes. PTTG overexpression is seen in several tumor types and correlates with survival time/recurrence. We evaluated PTTG expression in various types of brain tumors (n=94). Immunohistochemistry was performed using a monoclonal PTTG antibody (DCS‐280, Abcam;Cambridge, MA) and the streptavidin‐biotin‐peroxidase complex method. The intensity of PTTG immunoreactivity was evaluated semi‐quantitatively on a 0‐4 scale. PTTG expression was evident in most tumor cells and was predominantly nuclear. In glial tumors, PTTG immunoreactivity was higher in glioblastomas (IV), anaplastic oligoastrocytomas (III), anaplastic oligodendrogliomas (III), oligoastrocytomas (II), oligodendrogliomas (II), and pilocytic astrocytomas (I) (range: 3.1–3.5), whereas notably lower PTTG was seen in myxopapillary ependymomas (I) and ependymomas (II) (1.5 & 1.6). In non‐glial tumors, hemangiopericytomas and schwannomas had higher PTTG score (3.4), than meningiomas (2.3). Thus, it appears that PTTG expression is not associated with tumor grade, but rather with tumor type, the most striking difference being between ependymomas and other glial tumors. PTTG may be a valuable therapy target in some brain tumors. Acknowledgments Authors thank the Jarislowsky Foundation and the Lloyd‐Carr‐Harris Foundation for their generous support.

Ghrelin, a 28 amino acid‐containing orexigenic peptide, is an endogenous ligand of the GH secretagogue receptor. It was extracted from the rat stomach, but is present in other organs. The aim of this work was to localize ghrelin by immunohistochemistry in autopsy‐derived non‐tumorous human pituitaries. Immunohistochemistry was performed using the streptavidin‐biotin‐peroxidase complex method and the results were analyzed independently by 3 of the authors. Double Immunostaining was also undertaken to determine which cell type was expressing both the adenohypophysial hormone and ghrelin. Results showed that ghrelin can be localized in the adenohypophysis. It's immunoexpression being cytoplasmic, weak to moderate, and present in only a subset of cells. The neurohypophysis is immunonegative. Double immunostaining showed that ghrelin is co‐localized with GH, ACTH and LH and is present to 51–90% of such cells. PRL, TSH and FSH cells are consistently non‐reactive. The role of ghrelin in adenohypophysial endocrine activity is not clear. It may well be that ghrelin exerts an autocrine‐paracrine effect and can modulate hormone synthesis and release.

Ghrelin, an orexigenic hormone occurs mainly in stomach, and in several tumor types. We investigated ghrelin immunopositivity using the streptavidin‐biotin‐peroxidase complex method in the full spectrum of pituitary adenoma subtypes. Quantification was undertaken by analyzing both the percentage of tumor cells stained for ghrelin and the staining intensity. Cytoplasmic ghrelin immunopositivity was identified in several adenoma subtypes. Not every cell was immunopositive; the intensity of staining differed among cells within the given lesion and among the various tumors. The highest scores were noted in GH adenomas exposed to somatostatin analogues. In decreasing order, lower scores were encountered in ACTH‐producing, silent subtype 1 and 2 adenomas in Cushing disease, silent subtype 3 adenomas, untreated GH adenomas, dopamine agonist‐treated PRL adenomas, gonadotroph adenomas, and ACTH adenomas in Nelson syndrome. No immunoreactivity was found in TSH, untreated PRL‐producing, and null cell adenomas. The high immunoexpression of ghrelin in GH adenomas exposed to somatostatin analogues, may be due to increased ghrelin synthesis or to suppression of its release.