Effect of eicosapentaenoic acid,an omega-3 polyunsaturated fatty acid,on UVR-related cancer risk in humans. An assessment of early genotoxic markers

Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFAs) protect against photocarcinogenesis in animals, but prospective human studies are scarce. The mechanism(s) underlying the photoprotection are uncertain, although omega-3 PUFAs may influence oxidative stress. We examined the effect of supplementation on a range of indicators of ultraviolet radiation (UVR)-induced DNA damage in humans, and assessed effect on basal and post-UVR oxidative status. In a double-blind randomized study, 42 healthy subjects took 4 g daily of purified omega-3 PUFA, eicosapentaenoic acid (EPA), or monounsaturated, oleic acid (OA), for 3 months. EPA was bioavailable; the skin content at 3 months showing an 8-fold rise from baseline, P < 0.01. No consistent pattern of alteration in basal and UVR-exposed skin content of the antioxidants glutathione, vitamins E and C or lipid peroxidation, was seen on supplementation. Sunburn sensitivity was reduced on EPA, the UVR-induced erythemal threshold rising from a mean of 36 (SD 10) mJ/cm(2) at baseline to 49 (16) mJ/cm(2) after supplementation, P < 0.01. Moreover, UVR-induced skin p53 expression, assessed immunohistochemically at 24 h post-UVR exposure, fell from a mean of 16 (SD 5) positive cells/100 epidermal cells at baseline to 8 (4) after EPA supplementation, P < 0.01. Peripheral blood lymphocytes (PBL) sampled on 3 successive days both pre- and post-supplementation, showed no change with respect to basal DNA single-strand breaks or oxidative base modification (8-oxo-dG). However, when susceptibility of PBL to ex vivo UVR was examined using the comet assay, this revealed a reduction in tail moment from 84.4 (SD 3.4) at baseline to 69.4 (3.1) after EPA, P = 0.03. No significant changes were seen in any of the above parameters following OA supplementation. Reduction in this range of early markers, i.e. sunburn, UVR-induced p53 in skin and strand breaks in PBL, indicate protection by dietary EPA against acute UVR-induced genotoxicity; longer-term supplementation might reduce skin cancer in humans.     

Massive splenomegaly is associated with significant morbidity after laparoscopic splenectomy

OBJECTIVE: To evaluate the impact of spleen weight on operative and clinical outcome in a series of 108 consecutive laparoscopic splenectomies. BACKGROUND: Laparoscopic splenectomy as an alternative to open splenectomy for splenomegaly is regarded as controversial. METHODS: Patients underwent laparoscopic splenectomy for a range of hematological disorders between November 1992 and February 2000. Multiple linear and logistic regression analysis were used to assess the effect of massive splenomegaly (>1000 g) on perioperative mortality and morbidity, after adjusting for the joint effects of patient age, weight, pre- and postoperative full blood counts, operating time, estimated blood loss, conversion rate, reoperation rate, and duration of hospital stay. RESULTS: Massive splenomegaly was recorded in 27 of 108 (25%) cases. In this group, splenic weight ranged from 1000 to 4750 g (median, 2500 g). Patients with splenic weight >1000 g had a significantly longer median operating time (170 vs. 102 minutes, P < 0.01), conversion rate (5/27 vs. 4/81, P < 0.05), postoperative morbidity (15/27 vs. 4/81, P < 0.01), and median postoperative stay (5 vs. 3 days, P < 0.01). Multivariate analysis found splenic weight to be the most powerful predictor of morbidity (P < 0.01). Patients with splenomegaly (>1000 g) were 14 times likely to have post operative complications. One patient died 3 days after surgery, following a pulmonary embolus (spleen weight 500 g, mortality 1/108, 0.9%). CONCLUSIONS: Laparoscopic splenectomy is feasible in patients with giant spleens. However, it is associated with greater morbidity, and the advantages of minimal access surgery in this subgroup of patients are not so clear.     

Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells

Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. Increasing cAMP levels by GLP-1 potentiated glucose-induced Erk-1/2 phosphorylation via PKA activation. Elevation of [Ca(2+)](i) by glyburide potentiated Erk-1/2 phosphorylation, which was also inhibited by H89, suggesting increased [Ca(2+)](i) preceded PKA for glucose-induced Erk-1/2 activation. Adenoviral-mediated expression of dominant negative Ras in INS-1 cells decreased IGF-1-induced Erk-1/2 phosphorylation but had no effect on that by glucose. Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor."     

Improvement of laryngopharyngeal reflux symptoms after laparoscopic Hill repair

BACKGROUND: People with proven gastroesophageal reflux disease may also experience symptoms such as voice loss, chronic cough, globus, and sore throat. These laryngopharyngeal reflux symptoms have been reported to respond to prolonged proton pump inhibitor therapy, but the Hill approach to resolving these specific individual symptoms has not been widely reported in surgical literature. METHODS: This clinical outcome study is an analysis of symptom improvement in 145 patients who underwent laparoscopic Hill hiatal hernia repair. A standardized questionnaire was used to score eight gastroesophageal reflux disease symptoms and four laryngopharyngeal reflux symptoms. Also, each patient's primary chief complaints were analyzed. RESULTS: Gastroesophageal reflux and laryngopharyngeal reflux symptoms significantly improved (P < 0.01) compared with preoperative symptoms. Each patient's primary chief complaints improved as well. CONCLUSIONS: This clinical outcome analysis documents symptomatic improvement of laryngopharyngeal reflux and gastroesophageal reflux. Likewise, when these laryngopharyngeal reflux symptoms are chief complaints, with proven gastroesophageal reflux disease, the Hill approach to symptom resolution is likely to be successful.