University of Kentucky

About: University of Kentucky is a education organization based out in Lexington, Kentucky, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 43933 authors who have published 92195 publications receiving 3256087 citations. The organization is also known as: UK.

Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication

Abstract: SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. The WD40 repeat domain of Cdc4 binds with high affinity to a consensus phosphopeptide motif (the Cdc4 phospho-degron, CPD), yet Sic1 itself has many sub-optimal CPD motifs that act in concert to mediate Cdc4 binding. The weak CPD sites in Sic1 establish a phosphorylation threshold that delays degradation in vivo, and thereby establishes a minimal G1 phase period needed to ensure proper DNA replication. Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein–protein interactions.

Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology

Abstract: Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.

Laparoscopic repair of ventral hernias: nine years' experience with 850 consecutive hernias.

Abstract: One result of the 2 million laparotomies performed in the United States each year is an incisional hernia rate of 3% to 20%,1 necessitating repair of approximately 90,000 ventral hernias annually. Factors associated with formation of an incisional hernia include wound infection, immunosuppression, morbid obesity, previous operations, prostatism, and surgery for aneurysmal disease. Abdominal wall defects are typically observed within the first 5 years after the surgical incision is made, but they may develop long afterward.2 These hernias contribute importantly to the long-term morbidity of conventional surgery. Until techniques for the prevention of hernias are established, repair of these defects will remain an important problem for all abdominal surgeons. Many hernia repair methods have been described. Traditional primary repair entails a laparotomy with suture approximation of strong fascial tissue on each side of the defect. However, recurrence rates after this procedure range from 41% to 52% during long-term follow-up.2-4 Herniorrhaphies in which large prosthetic meshes are implanted appear to have lower failure rates (12-24%), but the required dissection of wide areas of soft tissue contributes to an increased incidence of wound infections and wound-related complications (12% or higher).3,5,6 These problems have stimulated a continuing search for new techniques for repairing ventral hernias. The interest in less morbid herniorrhaphies and the appeal of minimally invasive surgery encouraged development of laparoscopic methods for repairing incisional hernias. These techniques are based on the same physical and surgical principles as the open underlay procedure described by Stoppa,3 Rives et al,7 and Wantz.8 Since the first report of laparoscopic ventral hernia repair (LVHR) in 1992,9 the operation has grown in popularity with the belief that it may offer shorter hospital stays, improved patient outcomes, and fewer complications than traditional open procedures. Several comparative studies are now available that support this assertion.10-14 Limiting factors in most of these and the noncomparative series that describe LVHR include limited sample size, varying techniques, and restricted follow-up.15-18 We here describe a study of outcomes achieved with LVHR performed by 4 attending surgeons using the same surgical technique and standardized perioperative regimens and follow-up protocols. The reported series includes every patient in whom the operation was performed or attempted. Data on most patients were collected prospectively, and the follow-up time extends to more than 8 years. The goal of the study was to assess the safety and efficacy of LVHR.

Oxidative Alterations in Alzheimer's Disease

Abstract: There is increasing evidence that free radical damage to brain lipids, carbohydrates, proteins, and DNA is involved in neuron death in neurodegenerative disorders. The largest number of studies have been performed in Alzheimer's disease (AD) where there is considerable support for the oxidative stress hypothesis in the pathogenesis of neuron degeneration. In autopsied brain there is an increase in lipid peroxidation, a decline in polyunsaturated fatty acids (PUFA) and an increase in 4-hydroxynonenal (HNE), a neurotoxic aldehyde product of PUFA oxidation. Increased protein oxidation and a marked decline in oxidative-sensitive enzymes, glutamine synthetase and creatinine kinase, are found in the brain in AD. Increased DNA oxidation, especially 8-hydroxy-2′-deoxyguanosine (8-OHdG) is present in the brain in AD. Immunohistochemical studies show the presence of oxidative stress products in neurofibrillary tangles and senile plaques in AD. Markers of lipid peroxidation (HNE, isoprostanes) and DNA (8-OHdG) are increased in CSF in AD. In addition, inflammatory response markers (the complement cascade, cytokines, acute phase reactants and proteases) are present in the brain in AD. These findings, coupled with epidemiologic studies showing that anti-inflammatory agents slow the progression or delay the onset of AD, suggest that inflammation plays a role in AD. Overall these studies indicate that oxidative stress and the inflammatory cascade, working in concert, are important in the pathogenetic cascade of neurodegeneration in AD, suggesting that therapeutic efforts aimed at both of these mechanisms may be beneficial.