The TSH receptor and its role in thyroid disease

The thyrotropin (TSH) receptor plays a preeminent role in thyroid physiology and disease. TSH, acting through the TSH receptor, is the major stimulator of thyroid cell growth, differentiation and function. In Graves' disease, the TSH receptor is the target of stimulating antibodies that cause hyperthyroidism. Although still a topic of debate, the TSH receptor has been implicated in the pathogenesis of the endocrine ophthalmopathy associated with Graves' disease. Blocking antibodies against the TSH receptor are involved in the development of hypothyroidism in a subset of patients with autoimmune hypothyroidism. Transplacental passage of stimulating or blocking TSH receptor antibodies from a mother with autoimmune thyroid disease may result in transient hyper- or hypothyroidism in early infancy. During pregnancy, the placental hormone human choriogonadotropin (hCG) can cause gestational hyperthyroidism through cross-reaction with the TSH receptor. Gestational hyperthyroidism may also be involved in the pathogenesis of hyperemesis gravidarum. Trophoblast tumors secreting hCG are a rare cause of hyperthyroidism. Somatic activating mutations of the TSH receptor have been identified as a molecular cause of toxic adenomas, whereas activating mutations in the germline give rise to nonautoimmune familial hyperthyroidism or sporadic congenital hyperthyroidism. These gain-of-function mutations are dominant, and one mutated allele is sufficient to result in disease. Inactivating germline mutations of both TSH receptor alleles lead to variable degrees of resistance to TSH, encompassing a spectrum ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with thyroid hypoplasia. Received 31 January 2001; received after revision 3 April 2001; accepted 3 April 2001     

The role of periostin in tissue remodeling across health and disease

Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial–mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.     

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.     

The role of motile aeromonads in the fish disease, ulcerative disease syndrome (UDS)

Ulcerative Disease Syndrome (UDS) is an epizootic fish disease characterized by the presence of severe, open dermal ulcers on the head, midbody, and dorsal regions of the fish. Aeromonas hydrophila and A. sobria were recovered more often from UDS fish than other bacteria from the genera Vibrio, Alteromonas and Plesiomonas. Representative isolates of A. hydrophila, A. sobria, V. anguillarum, V. vulnificus, Alteromonas putrefaciens, and P. shigelloides taken from UDS and healthy fish were assayed for virulence-associated factors. The aeromonads produced a wide variety of hydrolytic enzymes and expressed cell surface characteristics linked to virulence whereas the other bacterial species rarely produced the same enzymes or cell surface characteristics. The role of aeromonads in UDS is believed to be opportunistic or secondary and these bacteria are thought to play an important role in this degenerative disease.     

Ferritin synthesis by splenic tumor tissue of Hodgkin's disease.

Increased ferritin synthesis by Hodgkin's disease splenic tumor tissue was demonstrated by incorporation of 14C-leucine and radioautography. This suggests that elevated tumor and serum ferritin concentrations found in patients with Hodgkin's disease is derived from tumor tissue per se.     

The location of soluble antigen in the spleen ofXenopus laevis

Résumé Une étude de la localisation de -globulines humaines (en solution saline) dans la rate deXenopus laevis a été effectuée en utilisant la fluorescence pour la détection d'antigènes. La thymectomie n'a eu aucun effet sur la première apparition d'antigènes dans la pulpe rouge entourant la zone de pulpe blanche.

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This work was supported by a Science Research Council Studentship. The author thanks Dr.M. J. Manning for advice and criticism.     

Leucine aminopeptase in the spleen

Zusammenfassung Leucinaminopeptidase wird histochemisch in der Milz von Mäusen und Ratten untersucht. Eine besonders ausgeprägte Reaktion zeigte sich in der Zentralarterienwandung und in den umgebenden Reticulumzellen der weissen Pulpa. Im Bereich der roten Pulpa verhalten sich nur die Inseln positiv, während eine extramedulläre Hämatopoese vorkommt.     

On the role of non-specific factors in the pathogenesis of infectious disease

Zusammenfassung Es wird einleitend darauf hingewiesen, dass mehr und mehr die Bedeutung von unspezifischen Faktoren für die Resistenz gegen Infektionen erkannt wird. Solche Faktoren können wohl auch in der Pathogenese von Infektionskrankheiten eine Rolle spielen, so zum Beispiel eine erhöhte Sensibilität gegen Endotoxin, die während den verschiedensten experimentellen Infektionen in Tieren nachgewiesen werden kann. An Hand von Experimenten an Mäusen wird dargestellt, in welchem Ausmass eine vorausgehende Impfung mit BCG den Ablauf einer nachfolgenden Infektion mitSalmonella typhimurium in verschiedenster Weise beeinflussen kann. Dies hängt weitgehend davon ab, ob grosse oder kleine Dosen zur Infektion verwendet werden.     

The origin of hemopoietic cells in ectopic implants of spleen and marrow

Summary Spleen and marrow tissues were cross-transplanted between CBA and CBA/HT6 mice. The majority of karyotypes in the regenerated implants were of recipient origin indicating that these implants are chimeric structures with the stroma of donor origin providing a framework for the proliferation of the recipient's hemopoietic stem cell.Supported by NIH Grant AM25510-01 and DOE contract 79EV00899. R. Khademi is currently with University of Isfahan, Iran.