Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications

ABSTRACT: BACKGROUND: AMP-activated protein kinase (AMPK) has recently been considered as a potential target for cancer therapy. However, the expression status of various subunits of the heterotrimeric AMPK in human cancers is rarely reported. We decided to determine their expressions in ovarian carcinomas and their relationships with the disease. METHODS: Expressions and locations of the AMPK-alpha1, -alpha2, -beta1, -beta2, -gamma1 and -gamma2 were detected by quantitative PCR (Q-PCR) and immunohistochemical staining (IHC). Their expression levels in ovarian tumors were compared with normal controls and also correlated with clinicopathological parameters. RESULTS: Except AMPK-alpha1, expressions of the other five AMPK subunits are significantly higher in ovarian carcinomas as determined by Q-PCR. Although IHC detection of AMPK-gamma1 and -gamma2 were not successful, over-expressions of AMPK-alpha2, -beta1, and -beta2 were further confirmed by IHC. Over-expressions of various AMPK subunits occurred independently and were mainly detected in the cytoplasm. Interestingly, AMPK-alpha2 and -beta1 were also detected in the nucleus and cell membrane, respectively. Clinical correlation analyses indicate that expressions of different AMPK subunits are associated with different subtypes of carcinoma. High expression of AMPK-alpha2 is significantly associated with endometrioid carcinomas. On the other hand, high expressions of AMPK-beta and -gamma subunits are associated with mucinous and serous carcinomas, respectively. Furthermore, high expressions of AMPK-beta1 and -gamma2 are also associated with early and late stages of disease, respectively. Finally, patients with high expression of AMPK-alpha2 had better prognosis. CONCLUSIONS: Aberrant expressions of AMPK subunits may play important roles in ovarian carcinogenesis. Each AMPK subunit may have its own function other than just a component of the AMPK molecule. Correlations with clinical parameters suggest that expressions of AMPK subunits have different clinical implications in ovarian cancer development.     

A systematic approach for identifying and presenting mechanistic evidence in human health assessments

Clear documentation of literature search and presentation methodologies can improve transparency in chemical hazard assessments. We sought to improve clarity for the scientific support for cancer mechanisms of action using a systematic approach to literature retrieval, selection, and presentation of studies. The general question was “What are the mechanisms by which a chemical may cause carcinogenicity in the target tissue?”. Di(2-ethylhexyl)phthalate was used as a case study chemical with a complex database of >3000 publications. Relevant mechanistic events were identified from published reviews. The PubMed search strategy included relevant synonyms and wildcards for DEHP and its metabolites, mechanistic events, and species of interest. Tiered exclusion/inclusion criteria for study pertinence were defined, and applied to the retrieved literature. Manual curation was conducted for mechanistic events with large literature databases. Literature trees documented identification and selection of the literature evidence. The selected studies were summarized in evidence tables accompanied by succinct narratives. Primary publications were deposited into the Health and Environmental Research Online (http://hero.epa.gov/) database and identified by pertinence criteria and key terms to permit organized retrieval. This approach contributes to human health assessment by effectively managing a large volume of literature, improving transparency, and facilitating subsequent synthesis of information across studies.     

Surgical management of blunt traumatic rupture of the descending thoracic aorta.

Acute rupture of the descending thoracic aorta following blunt trauma is a life-threatening injury that requires emergent operative intervention. From February 1989 to January 1997, 4 patients with multiple injuries including traumatic rupture in the region of the aortic isthmus were surgically treated at our institution. Diagnosis was confirmed in all patients by aortogram prior to aortic repair. One patient had preoperative paraplegia secondary to an unstable spinal fracture. All patients underwent repair under cardiopulmonary bypass (3 partial, 1 total with hypothermic arrest). The site of rupture was resected and replaced with an interposition artificial graft. There was no perioperative mortality and no additional occurrence of paraplegia. Our experience and a review of the literature indicate that for survivors of traumatic aortic rupture, excellent outcomes can be achieved only if the diagnosis is made early and the surgical treatment is prompt.     

Mechanisms underlying the inhibitory effect of propofol on the contraction of canine airway smooth muscle.

BACKGROUND: Propofol has been shown to produce relaxation of preconstricted airway smooth muscle. Although the inhibition of calcium mobilization is supposed to be the major mechanism of action, the whole picture of the mechanisms is not completely clear. METHODS: Contractile response was performed using canine tracheal rings. The effects of propofol on carbachol-induced mobilization of intracellular Ca2+ and phosphoinositide hydrolysis were measured using cultured canine tracheal smooth muscle cells by monitoring fura-2 signal and assessing the accumulation of [3H]-inositol phosphates. To detect the effect of propofol on muscarinic receptor density and affinity, [3H]N-methyl-scopolamine was used as a radioligand for receptor binding assay. RESULTS: Pretreatment with propofol shifts the concentration-response curves of carbachol-induced smooth muscle contraction to the right in a concentration-dependent manner without changing the maximal response. Propofol not only decreased the release of Ca2+ from internal stores but also inhibited the calcium influx induced by carbachol. In addition, carbachol-induced inositol phosphate accumulation was attenuated by propofol; the inhibitory pattern was similar to the contractile response. Moreover, propofol did not alter the density of muscarinic receptors. The dissociation constant value was not altered by pretreatment with 100 microM propofol but was significantly increased by 300 microM (propofol, 952+/-229 pM; control, 588+/-98 pM; P<0.05). CONCLUSIONS: Propofol attenuates the muscarinic receptor-mediated airway muscle contraction. The mechanism underlying these effects was attenuation of inositol phosphate generation and inhibition of Ca2+ mobilization through the inhibition of the receptor-coupled signal-transduction pathway.     

Effect of magnolol on in vitro mitochondrial lipid peroxidation and isolated cold-preserved warm-reperfused rat livers

BACKGROUND/AIM: A mechanism suggested to cause injury to preserved organs is the generation of oxygen free radicals. Lipid peroxidation is one of the biological damages caused by oxygen free radicals. It is our aim to investigate whether magnolol, a strong antioxidant, suppresses the generation of oxygen free radicals and improves the viability of cold-preserved warm-reperfused rat livers. MATERIALS AND METHODS: In vitro lipid peroxidation was induced in rat hepatic mitochondria with ADP and FeSO4. The inhibitory effect of magnolol on lipid peroxidation was measured with oxygen consumption and malondialdehyde (MDA) formation. Subsequently, we preserved and reperfused rat livers in preservation solutions that contained magnolol. The hepatic enzymes and liver MDA were measured to assess the protective effect of magnolol on isolated rat livers. RESULTS: In rat hepatic mitochondria, magnolol was 470 times more potent than alpha-tocopherol in inhibiting oxygen consumption and 340 times more potent than alpha-tocopherol in inhibiting MDA formation. Addition of magnolol to Ringer's lactate solution had a protective effect, in terms of MDA formation and leakage of hepatic enzymes, on warm-reperfused but not cold-stored liver tissue. Addition of magnolol to University of Wisconsin (UW) solution, a widely used preservation solution, did not modify the effect of this solution on isolated liver tissues. CONCLUSIONS: We conclude that magnolol is an effective antioxidant and suppresses lipid peroxidation in rat liver mitochondria and can be used as a rinsing solution in protecting transplanted organs from lipid peroxidation during reperfusion, especially for those organs not preserved with UW solution.     

Ex vivo comparative study using the Endolifter® as a traction device for enhancing submucosal visualization during endoscopic submucosal dissection

Background

Endoscopic submucosal dissection (ESD) is a technically demanding procedure, and exposure of the submucosa depends on the action of gravity and submucosal injection. The aim of the study was to investigate the effectiveness of the Endolifter^® as a traction device for enhancing submucosal visualization during ESD.

Methods

This was a prospective ex vivo comparative study conducted between September 2010 and March 2011 in the Prince of Wales Hospital. Consecutive ESDs were performed by four experienced endoscopists in an ex vivo ESD model with or without the Endolifter^®. The Endolifter^® allows simultaneous grasping, retracting and lifting of the mucosa during ESD, resulting in exposure of the submucosa. Each of the procedures were recorded and reviewed later by two independent assessors. The outcome measures included the proportion of time that the submucosa was visualized during the procedures (SM ratio), procedural times, perforation rates, amount of submucosal injections, and the difficulty of the procedure.

Results

Forty-eight gastric ESD procedures were performed on the model. The SM ratio was higher in the Endolifter^® group (P = 0.007), particularly for lesions located at the antrum (P < 0.001). The time required for submucosal dissection and the total procedural time were also less in the Endolifter^® group. The endoscopists rated the ESD procedures in the Endolifter^® group as less difficult (P = 0.033).

Conclusions

The Endolifter^® improved submucosal visualization during gastric ESD and reduces the difficulty of performing the procedures. The device may improve the ease of performing ESD in low-volume centers or large mucosal lesions.     

Revision endoscopic frontal sinus surgery with surgical navigation.

BACKGROUND: Revision surgery of the frontal sinus remains one of the most difficult operations for the endoscopic surgeon. Most agree that knowledge and recognition of its complex anatomy and sparing of frontal recess mucosa are keys to a successful operation. The use of surgical navigation systems may allow for more precise dissections and greater rates of frontal recess patency. METHODS: Retrospective review of all patients undergoing revision endoscopic frontal sinus surgery with surgical navigation was performed with a minimum 24-month follow-up. RESULTS: Sixty-seven patients underwent revision endoscopic frontal sinus surgery with surgical navigation. The average follow-up was 32 months. Fifty-eight (86.6%) had a patent frontal recess and significant subjective improvement in symptoms. No patient underwent external frontal sinus obliteration, and there were no major complications. CONCLUSIONS: Endoscopic techniques with surgical navigation are effective in revision frontal sinus cases. The dissection of remnant agger nasi, obstructing frontal and supraorbital cells are necessary to widen the anterior-posterior as well as the medial-lateral dimensions of the recess. Computer navigational systems appear to serve as a valuable adjunct in preoperative planning and safe intraoperative dissection.     

Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery

In this study, we evaluated the preemptive effect of a small dose of ketamine on postoperative wound pain. In a randomized, double-blinded, controlled trial, we compared the analgesic requirement in patients receiving preincision ketamine with ketamine after skin closure or placebo after gynecologic laparoscopic surgery. One-hundred-thirty-five patients were randomly assigned to receive preincision or postoperative ketamine 0.15 mg/kg or saline IV. Anesthetic technique was standardized. Patients were interviewed regularly up to 4 wk after surgery. Pain score, morphine consumption, side effects, and quality of recovery score were recorded. Patients receiving preincision ketamine had a lower pain score in the first 6 h after operation compared with the postoperative (P = 0.001) or placebo groups (P < 0.001). The mean (95% confidence intervals) time to first request for analgesia in the preincision group, 1.8 h (1.4-2.1), was longer than the postoperative group, 1.2 h (0.9-1.5; P < 0.001), or the placebo group, 0.7 h (0.4-0.9; P < 0.001). The mean +/- SD morphine consumption in the preincision group, 1.5 +/- 2.0 mg, was less than that in the postoperative group, 2.9 +/- 3.1 mg (P = 0.04) and the placebo group, 3.4 +/- 2.7 mg (P = 0.003). There was no significant difference among groups with respect to hemodynamic variables or side effects. No patient complained of hallucinations or nightmares. We conclude that a small dose of ketamine is not only safe, but it also provides preemptive analgesia in patients undergoing gynecologic laparoscopic surgery. IMPLICATIONS: In women undergoing laparoscopic gynecologic surgery, a small preoperative dose of ketamine (0.15 mg/kg) produced preemptive analgesia. There were no significant hemodynamic and psychological side effects with this dose.     

Posterior cruciate ligament-substituting total knee arthroplasty in young rheumatoid patients with advanced knee involvement

The integrity and strength of the posterior cruciate ligament (PCL) in the rheumatoid knee are known to be suboptimal. However, the results of PCL-substituting total knee arthroplasty in rheumatoid patients are not well documented. We reviewed 86 PCL-substituting total knee arthroplasties in 52 rheumatoid patients with grade IV or V radiographic disease. The mean age at surgery was 41.9 years. All patients underwent follow-up evaluation for an average of 7.8 years. Revision was performed for 1 knee because of aseptic loosening of the tibial component, and for 3 knees because of deep infection. An isolated insert exchange was performed on one knee. Using revision of any component for aseptic loosening or radiographic loosening as the end point, the mean 10-year survival rate was 94.0%.