Search

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

Hypoxic/ischemic trauma is a primary factor in the pathology of various vascular, pulmonary, and cerebral disease states. Yet, the signaling mechanisms by which cells respond and adapt to changes in oxygen levels are not clearly established. The effects of hypoxia on the stress-and mitogen-activated protein kinase (SAPK and MAPK) signaling pathways were studied in PC12 cells. Exposure to moderate hypoxia (5%O2) was found to progressively stimulate phosphorylation and activation of p38γ in particular, and also p38α. two isoforms of the p38 family of stress-activated protein kinases. In contrast, hypoxia had no effect on enzyme activity of p38β, p38β2, p38δ or on JNK, another stress-activated protein kinase. Prolonged hypoxia also induced phosphorylation and activation of p42/p44 MAPK, although this activation was modest when compared to NGF and UV-induced activation. We further showed that activation of p38γ and MAPK during hypoxia requires calcium, as treatment with Ca2+-free media or the calmodulin antagonist, W13, blocked the activation of p38γ and MAPK, respectively. These studies demonstrate that an extremely typical physiological stress (hypoxia) causes selective activation of specific elements of the SAPKs and MAPKs, and identifies Ca+2/CaM as a critical upstream activator.

Transplantation of dopamine-secreting cells harvested from fetal mesencephalon directly into the striatum has had limited success as a therapy for Parkinson's disease. A major problem is that the majority of the cells die during the first 3 weeks following transplantation. Hypoxia in the tissue surrounding the graft is a potential cause of the cell death. We have used subtractive cDNA libraries and microarray analysis to identify the gene expression profile that regulates tolerance to hypoxia. An improved understanding of the molecular basis of hypoxia-tolerance may allow investigators to engineer cells that can survive in the hypoxic environment of the brain parenchyma following transplantation.

The cellular response to hypoxia is complex. Specialized oxygen chemosensitive cells that are excitable respond to reduced O2 by membrane depolarization, altered gene expression, and neurotransmitter secretion. We have used the O2-sensitive pheochromocytoma (PC12) cell line to investigate the cellular response to hypoxia. Here, we present evidence that membrane depolarization and increased intracellular free Ca2+ are major regulatory events in these cells. Membrane depolarization is mediated by the inhibition of a slow-inactivating voltage-dependent potassium (K) channel. Evidence from molecular biology and patch-clamp studies indicate that the O2-sensitive K channel is a member of the Kv1 family. We also reviewed findings on the regulation of gene expression in PC12 cells during hypoxia. An increase in intracellular free Ca2+ is required for hypoxia-induced transcription of a number of genes including tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamine neurotransmitters, and several of the immediate early genes. We also reviewed the role of dopamine (DA) and adenosine (ADO) receptors in regulation of membrane depolarization and gene expression.

Several grazing systems were compared on the Diamond Mountain Cattle Allotment of the Ashley National Forest in Utah. The area is about 8,000 ft in elevation and receives 20-25 inches of precipitation annually. On native sagebrush-grass range, a comparison of summer-long (July-September) grazing every year, summer-long in alternate years, and 3-unit rest-rotation systems revealed no differences between systems in cover, production, or species composition of vegetation after 7 years of grazing. Average daily gains of cattle over the entire period were the same for all systems. During the period of study on this range, which was in fair to good condition and grazed at a moderate intensity, rest-rotation was not a better system than summer-long grazing. The key to this lack of difference was management. Rest-rotation systems require intensive management of water, salt, riding, etc. All units in both systems in the study had good distribution of water and salt and adequate riding to insure uniform cattle distribution. The unit grazed summer-long every year received the same degree of management and thus remained as productive as ranges under restrotation management. On seeded units of the allotment, heavy grazing in June in alternate years increased production on areas dominated by crested wheatgrass and smooth brome. Practical and efficient methods of managing cattle on highelevation ranges of the Intermountain area are needed. This study was started in 1959 and continued through 1967 and was designed to test two systems of spring (June) grazing on seeded mountain rangeland and three systems of summer grazing on native rangeland. The relative effects of the grazing systems on forage production, amount and pattern of utilization, ground cover, and cattle production were compared. It was a cooperative effort of the Diamond Mountain Cattle Association and the Intermountain Forest and Range Experiment Station and the Ashley National Forest of the U.S. Forest Service.