Systemic oxygen transport and erythropoiesis in the mouse

Summary Removal of 15% of blood volume in the mouse increases erythropoiesis by a factor of 2.2 when measured 12 h after bleeding. Exposure of normal mice to 40% reduced barometric pressure for the same period of time increases erythropoiesis only by a factor of 1.6. The response to hypoxia takes place in the presence of a 40% reduction of oxygen consumption and tissue-venous P_{o 2}, changes which are concomitant with a 5-fold increase in plasma erythropoietin activity. The larger response in anemic animals on the other hand occurs without any detectable change in these parameters. These results cast serious doubts about the interpretation of the quantitative homeostatic control of erythropoiesis based solely on the action of erythropoietin.Acknowledgments. This work was supported by a grant from the Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina. We thank Isabel Zingariello for excellent technical assistance.     

Glucose-6-phosphatase activity in experimental tuberculosis and following isoniazid treatment

Zusammenfassung Bei den tuberkulösen Meerschweinchen wurde in der Niere eine erhöhte Aktivität der Glukose-6-Phosphatase beobachtet. Isoniazid hat die erhöhte Aktivität des Enzyms nicht erniedrigt, wenn es tuberkulösen Tieren vom 8. bis zum 38. Tage nach der Infektion oral verabreicht wurde. Es wird angenommen, dass die erhöhte Aktivität Ausdruck der Adaptionsfähigkeit von Glukose-6-Phosphatase ist.

---

---

Galesburg State Research Hospital, Galesburg, Illinois, USA.     

History of the Lenz-Ising Model 1920–1950: From Ferromagnetic to Cooperative Phenomena

I chart the considerable changes in the status and conception of the Lenz-Ising model from 1920 to 1950 in terms of three phases: In the early 1920s, Lenz and Ising introduced the model in the field of ferromagnetism. Based on an exact derivation, Ising concluded that it is incapable of displaying ferromagnetic behavior, a result he erroneously extended to three dimensions. In the next phase, Lenz and Isings contemporaries rejected the model as a representation of ferromagnetic materials because of its conflict with the new quantum mechanics. In the third phase, from the early 1930s to the early 1940s, the model was revived as a model of cooperative phenomena. I provide more detail on this history than the earlier accounts of Brush (1967) and Hoddeson, Schubert, Heims, and Baym (1992) and question some of their conclusions. Moreover, my account differs from these in its focus on the development of the model in its capacity as a model. It examines three aspects of this development: (1) the attitudes on the degree of physical realism of the Lenz-Ising model in its representation of physical phenomena; (2) the various reasons for studying and using it; and (3) the effect of the change in its theoretical basis during the transition from the old to the new quantum mechanics. A major theme of my study is that even though the Lenz-Ising model is not fully realistic, it is more useful than more realistic models because of its mathematical tractability. I argue that this point of view, important for the modern conception of the model, is novel and that its emergence, while perhaps not a consequence of its study, is coincident with the third phase of its development.     

TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.     

Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.     

Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs

Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALXbeta-cadherin motif is important for normal functioning of FREM2.