The social and medical costs of the biological aging process are high and will rise rapidly in coming decades, creating an enormous challenge to societies worldwide. In recent decades, researchers have expanded their understanding of the underlying deleterious structural and physiological changes (aging damage) that underlie the progressive functional impairments, declining health, and rising mortality of aging humans and other organisms and have been able to intervene in the process in model organisms, even late in life. To preempt a global aging crisis, we advocate an ambitious global initiative to translate these findings into interventions for aging humans, using three complementary approaches to retard, arrest, and even reverse aging damage, extending and even restoring the period of youthful health and functionality of older people.
Although there are limited effective measures to improve functional status, preventive strategies that include smoking cessation and pneumococcal vaccination should be actively pursued. Routine evaluation of swallowing dysfunction and use of pharmacological agents to improve the cough reflex deserve further evaluation in multicenter controlled trials.
Pulmonary arterial hypertension associated with portal hypertension occurs in about 5% of patients being evaluated for liver transplantation. Treatment is required to facilitate safe transplantation, and oral pulmonary vasodilators have yet to be prospectively evaluated for this disease. The objective of this study was to determine the hemodynamic outcome in a consecutive cohort of patients offered sildenafil as first-line treatment for portopulmonary hypertension. We identified consecutive patients at the University of Rochester referred by the liver transplant team. All had catheter-confirmed disease and were treated with sildenafil. Patients were excluded from analysis if they did not have follow-up catheterizations. The change in pulmonary vascular resistance at the time of first follow-up was the primary outcome. Eleven patients began sildenafil, and 9 had follow-up right heart catheterizations during a 3-year period. Pulmonary vascular resistance dropped in each patient; as a group, the mean dropped from 575 to 375 dynes/second/cm 5 . Four of 9 patients achieved a mean pulmonary artery pressure Յ 35 mm Hg at the time of first recatheterization, and 1 patient received a successful cadaveric transplant. Four of 6 patients with more than 1 follow-up catheterization had sustained hemodynamic benefit. One patient initially responded to therapy with favorable hemodynamics but was found in the operating room to have recrudescent disease (on therapy) that precluded safe transplantation. In conclusion, sildenafil was associated with improved hemodynamics in this small, uncontrolled cohort. A multicenter, prospective evaluation is warranted in this group uniformly excluded from phase III clinical trials. Liver Transpl 15:30-36, 2009.
Objective-Arginine deficiency may contribute to microvascular dysfunction, but previous studies suggest that arginine supplementation may be harmful in sepsis. Systemic arginine availability can be estimated by measuring the ratio of arginine to its endogenous inhibitors, asymmetric and symmetric dimethylarginine. We hypothesized that the arginine to dimethylarginine (Arg/DMA) ratio is reduced in patients with severe sepsis and associated with severity of illness and outcomes.Design-Case-control and prospective cohort study This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptCrit Care Med. Author manuscript; available in PMC 2012 June 1. Conclusions-The Arg/DMA ratio is associated with severe sepsis, severity of illness, and clinical outcomes. The Arg/DMA ratio may be a useful biomarker, and interventions designed to augment systemic arginine availability in severe sepsis may still be worthy of investigation.
Objective Nitric oxide (NO) deficiency may contribute to microvascular dysfunction in sepsis. Current physiologic paradigms contend that nitrite and/ or S-nitrosohemoglobin (SNOHb) mediate intravascular delivery of NO. These NO metabolites are purportedly consumed during hemoglobin deoxygenation producing NO and coupling intravascular NO delivery with metabolic demand. Systemic nitrite and SNOHb consumption can be assessed by comparing their concentrations in arterial vs. venous blood. We hypothesized that arterial vs. venous (A-V) differences in nitrite and SNOHb are diminished in sepsis and associated with mortality. Design Case-control and prospective cohort study Setting Adult intensive care units of an academic medical center Patients and subjects 87 critically ill septic patients and 52 control subjects Interventions None Measurements and Main Results Nitrite and SNOHb were measured using tri-iodide-based reductive chemiluminescence. In control subjects, arterial plasma, whole blood and red blood cell nitrite levels were higher than the corresponding venous levels. In contrast, SNOHb was higher in venous compared to arterial blood. In septic patients, A-V RBC nitrite and SNOHb differences were absent. Moreover, the plasma nitrite A-V difference was absent in non-survivors. Conclusions In health, nitrite levels are higher in arterial vs. venous blood (suggesting systemic nitrite consumption) whereas SNOHb levels are higher in venous vs. arterial blood (suggesting systemic SNOHb production). These A-V differences are diminished in sepsis, and diminished A-V plasma nitrite differences are associated with mortality. These data suggest pathologic disruption of systemic nitrite utilization in sepsis.
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