Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice

Abstract Recent landmark molecular genetic studies have identified an evolutionarily conserved insulin/IGF-1 signal transduction pathway that regulates lifespan. In C. elegans, Drosophila, and rodents, attenuated insulin/IGF-1 signaling appears to regulate lifespan and enhance resistance to environmental stress. The Ames (Prop1 df/df ) and Snell (Pit1 dw/dw ) hypopituitary dwarf mice with growth hormone (GH), thyroidstimulating hormone (TSH), and prolactin deficiencies live 40-60% longer than control mice. Both mutants are resistant to multiple forms of environmental stress in vitro. Taken collectively, these genetic models indicate that diminished insulin/IGF-l signaling may play a central role in the determination of mammalian lifespan by conferring resistance to exogenous and endogenous stressors. These pleiotropic endocrine pathways control diverse programs of gene expression that appear to orchestrate the development of a biological phenotype that promotes longevity. With the ability to investigate thousands of genes simultaneously, several microarray surveys have identified potential longevity assurance genes and provided information on the mechanism(s) by which the dwarf genotypes (dw/dw) and (df/df), and caloric restriction may lead to longevity. We propose that a comparison of specific changes in gene expression shared between Snell and Ames dwarf mice may provide a deeper understanding of the transcriptional mechanisms of longevity determination. Furthermore, we propose that a comparison of the physiological consequences of the Pit1dw and Prop1df mutations may reveal transcriptional profiles similar to those reported for the C. elegans and Drosophila mutants. In this study we have identified classes of genes whose expression is similarly affected in both Snell and Ames dwarf mice. Our comparative microarray data suggest that specific detoxification enzymes of the P 450 (CYP) family as well as oxidative and steroid metabolism may play a key role in longevity assurance of the Snell and Ames dwarf mouse mutants. We propose that the altered expression of these genes defines a biochemical phenotype which may promote longevity in Snell and Ames dwarf mice

Tumor necrosis factor-α and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis

Background: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)α is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNFα/ROs on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC

Peripheral capillary non-perfusion in asymptomatic Waldenström's macroglobulinemia

<p>Abstract</p> <p>Background</p> <p>To report the rare association of peripheral retinal ischemia in a patient with Waldenström's macroglobulinemia.</p> <p>Case Presentation</p> <p>A 39-year old man with a recent diagnosis of asymptomatic Waldenström's macroglobulinemia (WM) was referred from his physician for ocular evaluation. The fundus examination in his right eye (RE) revealed very mild central vein dilation, while retinal hemorrhages associated with microaneurismal alterations of the vascular plexus were detected at the temporal periphery. Fluoroscein angiography of his RE revealed an extended area of capillary dropout distal to the microaneurismal lesions. In our patient with WM an extensive area of capillary non-perfusion, in the absence of severe involvement of the posterior pole was documented; this association to the best of our knowledge has never been reported before.</p> <p>Conclusion</p> <p>Although the incidence of the disease is rare, meticulous examination of the retinal periphery should be performed in all patients with WM and vice versa the differential diagnosis of peripheral retinal ischemia of unknown origin should include an investigation to rule out asymptomatic Waldenström's macroglobulinemia.</p

Ishemia-Reperfusion enhances GAPDH nitration in aging skeletal muscle

Aging and skeletal muscle ischemia/reperfusion (I/R) injury leads to decreased contractile force generation that increases severely with age. Our studies show that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein expression is significantly decreased at 3 and 5 days reperfusion in the young mouse muscle and at 1, 3, 5, and 7 days in the aged muscle. Using PCR, we have shown that GAPDH mRNA levels in young and old muscle increase at 5 days reperfusion compared to control, suggesting that the protein deficit is not transcriptional. Furthermore, while total tyrosine nitration did not increase in the young muscle, GAPDH nitration increased significantly at 1 and 3 days reperfusion. In contrast, total tyrosine nitration in aged muscle increased significantly at 1, 3, and 5 days of reperfusion, with increases in GAPDH nitration at the same time points. We conclude that GAPDH protein levels decrease following I/R, that this is not transcriptionally mediated, that the aged muscle experiences greater oxidative stress, protein modification and GAPDH degradation, possibly contributing to decreased muscle function. We propose that tyrosine nitration enhances GAPDH degradation following I/R and that the persistent decrease of GAPDH in aged muscle is due to the prolonged increase in oxidative modification in this age group

Impact of a novel surgical wound protection device on observed versus expected surgical site infection rates after colectomy using the National Surgical Quality Improvement Program Risk Calculator

Surgical site infection (SSI) remains a persistent and morbid problem in colorectal surgery. A novel surgical device that combines barrier surgical wound protection and continuous surgical wound irrigation was evaluated in a cohort of elective colorectal surgery patients. A retrospective analysis was performed comparing rates of SSI observed in a prospective cohort study with the predicted rate of SSI using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Risk Calculator.A prospective multi-center study of colectomy patients was conducted using a study device for surgical site retraction and protection, as well as irrigation of the incision. Patients were followed for 30 days after the surgical procedure to assess for SSI. After completion of the study, patients' characteristics were inserted into the ACS-NSQIP Risk Calculator to determine the predicted rate of SSI for the given patient population and compared with the observed rate in the study.A total of 108 subjects were enrolled in the study. The observed rate of SSI in the prospective study using the novel device was 3.7% (4/108). The predicted rate of SSI in the same patient population utilizing the ACS-NSQIP Risk Calculator was estimated to be 9.5%. This demonstrated a 61% difference (3.7% vs. 9.5%, p = 0.04) in SSI from the NSQIP predicted rate with the use of the irrigating surgical wound protection and retraction device.These data suggest the use of a novel surgical wound protection device seems to reduce the rate of SSIs in colorectal surgery

Management dilemma; a woman with cystic fibrosis and severe lung disease presenting with colonic carcinoma: a case report

Introduction There are increasing reports of bowel cancer in cystic fibrosis, suggesting a possible causal link. Individuals with cystic fibrosis who have advanced lung disease present a high operative risk, limiting curative treatment options in early bowel malignancy. Case presentation We describe a 41-year-old Caucasian woman with cystic fibrosis and severe lung disease who had been considered for lung transplantation, who presented with rectal bleeding and was found to have a Stage I adenocarcinoma of the sigmoid colon. After considerable discussion as to the operative risks, she underwent a laparoscopic resection and remains relatively well 1 year postoperatively with no recurrence. Conclusion We discuss the complexity of the management decisions for cystic fibrosis patients with severe lung disease and early stage colonic malignancy, particularly in the context of potential need for lung transplantation. The case demonstrates that cystic fibrosis patients with very severe lung function impairment may undergo laparoscopic abdominal surgical interventions without compromising postoperative airway clearance

Cube law, condition factor and weight-length relationships: history, meta-analysis and recommendations

This study presents a historical review, a meta-analysis, and recommendations for users about weight–length relationships, condition factors and relative weight equations. The historical review traces the developments of the respective concepts. The meta-analysis explores 3929 weight–length relationships of the type W = aLb for 1773 species of fishes. It shows that 82% of the variance in a plot of log a over b can be explained by allometric versus isometric growth patterns and by different body shapes of the respective species. Across species median b = 3.03 is significantly larger than 3.0, thus indicating a tendency towards slightly positive-allometric growth (increase in relative body thickness or plumpness) in most fishes. The expected range of 2.5 < b < 3.5 is confirmed. Mean estimates of b outside this range are often based on only one or two weight–length relationships per species. However, true cases of strong allometric growth do exist and three examples are given. Within species, a plot of log a vs b can be used to detect outliers in weight–length relationships. An equation to calculate mean condition factors from weight–length relationships is given as Kmean = 100aLb−3. Relative weight Wrm = 100W/(amLbm) can be used for comparing the condition of individuals across populations, where am is the geometric mean of a and bm is the mean of b across all available weight–length relationships for a given species. Twelve recommendations for proper use and presentation of weight–length relationships, condition factors and relative weight are given