Oxygen affinity of hemoglobin and peripheral nerve degeneration in experimental diabetes

Peripheral neuropathy remains a major complication of diabetes. Numerous etiological theories of metabolic and/or vascular disturbances have been suggested including decreased endoneurial oxygen tension with presumed tissue hypoxia. Increases in the affinity of hemoglobin for oxygen (Hb-O2 affinity) may also produce tissue hypoxia and such Hb-O2 affinity changes have been implicated in the pathogenesis of diabetic microangiopathy. In order to test whether affinity hypoxia might contribute to the development of diabetic peripheral neuropathy, we have utilized a rat model of high and normal Hb-O2 affinity produced by backcrossing animals with increased and decreased levels of 2,3-diphosphoglycerate (DPG). Diabetes was induced in ten high and ten low DPG animals with a tail vein injection of 55 mg/kg streptozotocin (STZ). Five animals in each group were treated with 2.4 U protamine zinc insulin (PZI)/day while the remaining animals were untreated. All rats were killed after 30 days, sections of tibial and sural nerve were rapidly removed and processed for teased fiber analysis. A minimum of 125 axons were assessed per nerve for E degeneration (myelin ovoids) using the classification developed by Dyck et al. Untreated animals, regardless of DPG levels, demonstrated 0% neuropathy. In contrast, all insulin-treated animals showed degeneration (0.4-17%) that inversely correlated with the DPG level (r = -0.59, P 2 affinity) with its attendant effect on tissue oxygen release may play a role in the development of peripheral neuropathy in STZ-induced diabetic rats treated with insulin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29479/1/0000565.pd

On Babylonian lavatories and sewers

This study begins by examining the archaeological and documentary evidence for lavatories (toilets) and foul-water drains in ancient Mesopotamian dwelling houses. It goes on to investigate the use, etymology and history of the Akkadian word asurrû: in the Old Babylonian period it served mainly as a term for a kind of foul-water drain or “sewer” but later shed that meaning

Private Sector Union Density and the Wage Premium: Past, Present, and Future

The rise and decline of private sector unionization were among the more important features of the U.S. labor market during the twentieth century. Following a dramatic spurt in unionization after passage of the depression-era National Labor Relations Act (NLRA) of 1935, union density peaked in the mid-1950s, and then began a continuous decline. At the end of the century, the percentage of private wage and salary workers who were union members was less than 10 percent, not greatly different from union density prior to the NLRA

Behavioral Consequences of NMDA Antagonist-Induced Neuroapoptosis in the Infant Mouse Brain

Background: Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia. Methodology/Principal Findings: We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP), or saline, on postnatal day 2 (P2) or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7. Conclusions: These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathologica

Pathogenesis of myonecrosis induced by crude venom and a myotoxin of Bothrops asper.

The pathogenesis of skeletal muscle necrosis induced by crude Bothrops asper venom and isolated myotoxic phospholipase was studied using light and electron microscopy. White mice were injected intramuscularly with a dose of 2.5 micrograms/g and tissue samples were taken at 30 min and 1, 3, 6, 12, 24, and 48 hr. Toxin-injected muscle showed localized wedge-shaped lesions ("delta lesions") by 30 min, which included disrupted plasma membranes. At 1 and 3 hr the predominant type of necrotic cell contained clumped myofibrils in which individual myofilaments were indistinguishable. At later time periods there was a relaxation and redistribution of myofilaments resulting in a more homogeneous and hyaline appearance of necrotic cells. Some mitochondria were swollen and had flocculent densities, and most of them were disrupted, having only one membrane and vesiculated cristae. The basal lamina was intact at all time intervals. Phagocytosis of muscle cell debris started at 3 hr and was prominent by 24-48 hr. In crude venom-injected muscle many cells showed pathologic features identical to those observed after myotoxin injection. Crude venom also induced hemorrhage which was evident 30 min after injection, reaching its highest level by 12 hr. At 3, 6, and 12 hr some cells were undergoing different pathologic changes which appeared to be due to ischemia. Although these cells were irreversibly damaged, as indicated by ruptured plasma membrane, their myofibrillar structure was better preserved than that of toxin-affected cells. The Z line was absent, but A, I, H, and M bands were intact. As a result of Z line loss, sarcomeres were disoriented. It is proposed that the myotoxin induces myonecrosis by first altering the integrity of the plasma membrane, thereby increasing the permeability to calcium, other ions, and molecules which leads to death of the cell. Crude venom affects muscle cells in two ways: by direct action of myotoxin (s) and by ischemia due to hemorrhage.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

BACKGROUND: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF

Extrinsic Rewards and Intrinsic Motives: Standard and Behavioral Approaches to Agency and Labor Markets

Employers structure pay and employment relationships to mitigate agency problems. A large literature in economics documents how the resolution of these problems shapes personnel policies and labor markets. For the most part, the study of agency in employment relationships relies on highly stylized assumptions regarding human motivation, e.g., that employees seek to earn as much money as possible with minimal effort. In this essay, we explore the consequences of introducing behavioral complexity and realism into models of agency within organizations. Specifically, we assess the insights gained by allowing employees to be guided by such motivations as the desire to compare favorably to others, the aspiration to contribute to intrinsically worthwhile goals, and the inclination to reciprocate generosity or exact retribution for perceived wrongs. More provocatively, from the standpoint of standard economics, we also consider the possibility that people are driven, in ways that may be opaque even to themselves, by the desire to earn social esteem or to shape and reinforce identity