Ghrelin for cachexia

Ghrelin, a natural ligand for the growth hormone (GH)-secretagogue receptor, is primarily produced in the stomach. Administration of ghrelin stimulates food intake and GH secretion in both animals and humans. Ghrelin is the only circulating hormone known to stimulate appetite in humans. As GH is an anabolic hormone, protein stores are spared at the expense of fat during conditions of caloric restriction. Ghrelin also inhibits the production of anorectic proinflammatory cytokines. Thus, ghrelin exhibits anti-cachectic actions via both GH-dependent and -independent mechanisms. Several studies are evaluating the efficacy of ghrelin in the treatment of cachexia caused by a variety of diseases, including congestive heart failure, chronic obstructive pulmonary disease, cancer, and end-stage renal disease. These studies will hopefully lead to the development of novel clinical applications for ghrelin in the future. These studies have also facilitated a better understanding of the molecular basis of the anti-catabolic effects of ghrelin. This review summarizes the recent advances in this area of research

Ghrelin and Functional Dyspepsia

The majority of patients with dyspepsia have no identifiable cause of their disease, leading to a diagnosis of functional dyspepsia (FD). While a number of different factors affect gut activity, components of the nervous and endocrine systems are essential for normal gut function. Communication between the brain and gut occurs via direct neural connections or endocrine signaling events. Ghrelin, a peptide produced by the stomach, affects gastric motility/emptying and secretion, suggesting it may play a pathophysiological role in FD. It is also possible that the functional abnormalities in FD may affect ghrelin production in the stomach. Plasma ghrelin levels are reported to be altered in FD, correlating with FD symptom score. Furthermore, some patients with FD suffer from anorexia with body-weight loss. As ghrelin increases gastric emptying and promotes feeding, ghrelin therapy may be a new approach to the treatment of FD

Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves’ Disease

Graves’ disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments

Epitope Recognition in HLA-DR3 Transgenic Mice Immunized to TSH-R Protein or Peptides

Development of Graves\u27 disease is related to HLA-DR3. The extracellular domain (ECD) of human TSH receptor (hTSH-R) is a crucial antigen in Graves\u27 disease. hTSH-R peptide 37 (amino acids 78–94) is an important immunogenic peptide in DR3 transgenic mice immunized to hTSH-R. This study examined the epitope recognition in DR3 transgenic mice immunized to hTSH-R protein and evaluated the ability of a mutant hTSH-R peptide to attenuate the immunogenicity of hTSH-R peptide 37. DR3 transgenic mice were immunized to recombinant hTSH-R-ECD protein or peptides. A mutant hTSH-R 37 peptide (ISRIYVSIDATLSQLES: 37m), in which DR3 binding motif position 5 was mutated V\u3eA, and position 8 Q\u3eS, was synthesized. 37m should bind to HLA-DR3 but not bind T cell receptors. DR3 transgenic mice were immunized to hTSH-R 37 and 37m. Mice immunized to hTSH-R-ECD protein developed strong anti-hTSH-R antibody, and antisera reacted strongly with hTSH-R peptides 1–5 (20–94), 21 (258–277), 41 (283–297), 36 (376–389), and 31 (399–418). Strikingly, antisera raised to hTSH-R peptide 37 bound to hTSH-R peptides 1–7 (20–112), 10 (132–50), 33 (137–150), 41, 23 (286–305), 24 (301–320), 36, and 31 as well as to hTSH-R-ECD protein. Both antibody titers to hTSH-R 37 and reaction of splenocytes to hTSH-R 37 were significantly reduced in mice immunized to hTSH-R 37 plus 37m, compared with mice immunized to hTSH-R 37 alone. The ability of immunization to a single peptide to induce antibodies that bind hTSH-R-ECD protein, and multiple unrelated peptides, is a unique observation. Immunogenic reaction to hTSH-R peptide 37 was partially suppressed by 37m, and this may contribute to immunotherapy of autoimmune thyroid disease

Successful Treatment of Protein-Losing Gastroenteropathy with Steroid Pulse and Immunosuppressive Therapies in a Patient with Sjögren Syndrome

We report the case of a 59-year-old female who developed facial edema together with hypoproteinemia. On the basis of 99mTc-human serum albumin scintigraphy and a1-antitrypsin clearance, she was diagnosed with protein-losing gastroenteropathy. Furthermore, she was diagnosed with Sjögren syndrome on the basis of eye and oral dryness, positive result with anti-SSA antibody, and salivary gland biopsy. Her symptoms improved with the use of immunosuppressive agents following steroid pulse therapy. Therefore, steroid pulse therapy and immunosuppressive agents should be considered as possible effective treatment strategies for protein-losing gastroenteropathy associated with autoimmune diseases

Thyroid ultrasound findings in a follow-up survey of children from three Japanese prefectures: Aomori, Yamanashi, and Nagasaki

We conducted ultrasound thyroid screening in cohort of 4,365 children aged between 3 to 18 years in three Japanese prefectures (Aomori, Yamanashi, and Nagasaki) using the same procedures as used in the Fukushima Health Survey. Forty-four children had nodules ? 5.1 mm in diameter or cysts ? 20.1 mm in diameter detected at the first screening, and 31 of these children underwent the second follow-up survey. We collected information from thyroid ultrasound examinations and final clinical diagnoses and re-categorized the thyroid findings after the second examination. Twenty children had nodules ? 5.1 mm in diameter or cysts ? 20.1 mm in diameter at the second examination; of these, one child was diagnosed with a thyroid papillary carcinoma and the remaining 19 children were diagnosed with possibly benign nodules such as adenomas, adenomatous nodules, and adenomatous goiters. A further 11 children were re-categorized as "no further examinations were required." Our results suggest that ultrasound thyroid findings in children may change with a relatively short-term passing period, and that thyroid cancer may exist at a very low but certain frequency in the general childhood population

Thyroid Ultrasound Findings in Children from Three Japanese Prefectures: Aomori, Yamanashi and Nagasaki

Due to the likelihood of physical and mental health impacts following the unprecedented accident at the Fukushima Daiichi Nuclear Power Plant, the Fukushima prefectural government decided to conduct the Fukushima Health Management Survey to assist in the long-term health management of residents. This included thyroid ultrasound examination for all children in Fukushima. For appropriate evaluation of ultrasound screening of the thyroid, it is important to understand its reference data of thyroid findings in children in general. In order to analyze the frequencies of specific thyroid findings, we conducted ultrasound screening of the thyroid by the same procedures as used in Fukushima in 4,365 children, aged 3 to 18 years, from three Japanese prefectures. Overall, thyroid cysts were identified in 56.88% and thyroid nodules in 1.65% of the participants. Thyroid cysts and nodules with a maximum diameter of more than 5 mm were identified in 4.58% and 1.01%, respectively, and age-adjusted prevalences were 3.82% and 0.99%, respectively. Although the prevalence of cysts and nodules varied among the examination areas, no significant differences were observed among the three examination areas in the prevalence of cysts and nodules with a maximum diameter of more than 5 mm. Also, the prevalence of thyroid cysts and nodules, especially those with a maximum diameter of more than 5 mm, significantly increased with age, and showed a female predominance. We also identified ectopic thymus (1.95%), diffuse goiter (1.40%), ultimobranchial body (0.73%), lymph node swelling (0.21%) and thyroid agenesis (0.05%). This is the first ultrasound description of the age-adjusted prevalence of thyroid cysts and nodules, or of the prevalence of abnormalities other than cysts and nodules, such as ectopic thymus, in relation to age, in the general Japanese child population. We contend that this can provide relevant information for the Fukushima Health Management Survey and future population studies

The physiological significance and potential clinical applications of ghrelin.

Ghrelin, a natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is now known to play a role in a number of different physiological processes. For example, ghrelin increases GH secretion, feeding, and body weight when administered centrally or peripherally. These unique effects of ghrelin should be invaluable for the development of novel treatments and disease diagnostic techniques. Clinical trials have already been performed to assess the utility of ghrelin for the treatment of several disorders including anorexia, cachexia, and GH-related disorders. This review summarizes the recent advances in this area of research

Cumulative number of registrants with thyroid storm

Prospective Multicenter Registry–Based Study on Thyroid Storm: Cumulative number of registrants with thyroid storm from May 1, 2018 to April 30, 2022.*, Four of them, who did not satisfy JTA diagnostic criteria, were excluded from this study.</p

Appendix:<b>REDCap online survey questionnaire</b> of thyroid storm.docx

Prospective Multicenter Registry–Based Study on Thyroid Storm</p