Reduced lactate dehydrogenase activity in the heart and suppressed sex hormone levels are associated with female-biased mortality during thermal stress in Pacific salmon.

Female-biased mortality has been repeatedly reported in Pacific salmon during their upriver migration in both field studies and laboratory holding experiments, especially in the presence of multiple environmental stressors, including thermal stress. Here, we used coho salmon (Oncorhynchus kisutch) to test whether females exposed to elevated water temperatures (18°C) (i) suppress circulating sex hormones (testosterone, 11-ketotestosterone and estradiol), owing to elevated cortisol levels, (ii) have higher activities of enzymes supporting anaerobic metabolism (e.g. lactate dehydrogenase, LDH), (iii) have lower activities of enzymes driving oxidative metabolism (e.g. citrate synthase, CS) in skeletal and cardiac muscle, and (iv) have more oxidative stress damage and reduced capacity for antioxidant defense [lower catalase (CAT) activity]. We found no evidence that a higher susceptibility to oxidative stress contributes to female-biased mortality at warm temperatures. We did, however, find that females had significantly lower cardiac LDH and that 18°C significantly reduced plasma levels of testosterone and estradiol, especially in females. We also found that relative gonad size was significantly lower in the 18°C treatment regardless of sex, whereas relative liver size was significantly lower in females held at 18°C. Further, relative spleen size was significantly elevated in the 18°C treatments across both sexes, with larger warm-induced increases in females. Our results suggest that males may better tolerate bouts of cardiac hypoxia at high temperature, and that thermal stress may also disrupt testosterone- and estradiol-mediated protein catabolism, and the immune response (larger spleens), in migratory female salmon.

Using a structured questionnaire improves seizure description by medical students.

OBJECTIVE: The purpose of this study was to evaluate a structured questionnaire for improving a medical students' ability to identify, describe and interpret a witnessed seizure. METHODS: Ninety two 3rd year medical students, blinded to seizure diagnosis, viewed videos of a primary generalized seizure and a complex partial seizure. Students next completed an unstructured questionnaire that asked the students to describe the seizure video recordings. The students then completed a structured questionnaire that asked the student to respond to 17 questions regarding specific features occurring during the seizures. We determined the number and types of correct responses for each questionnaire. RESULTS: Overall, the structured questionnaire was more effective in eliciting an average of 9.25 correct responses compared to the unstructured questionnaire eliciting an average of 5.30 correct responses (p < 0.001). Additionally, 10 of the 17 seizure features were identified more effectively with the structured questionnaire. Potentially confounding factors, prior knowledge of someone with epilepsy or a prior experience of viewing a seizure, did not predict the student's ability to correctly identify any of the 17 features. CONCLUSIONS: A structured questionnaire significantly improves a medical student's ability to provide an accurate clinical description of primary generalized and complex partial witnessed seizures. Our analysis identified the 10 specific features improved by using the structured questionnaire.

Similar patterns of frequency-dependent selection on animal personalities emerge in three species of social spiders.

Frequency-dependent selection is thought to be a major contributor to the maintenance of phenotypic variation. We tested for frequency-dependent selection on contrasting behavioural strategies, termed here 'personalities', in three species of social spiders, each thought to represent an independent evolutionary origin of sociality. The evolution of sociality in the spider genus Anelosimus is consistently met with the emergence of two temporally stable discrete personality types: an 'aggressive' or 'docile' form. We assessed how the foraging success of each phenotype changes as a function of its representation within a colony. We did this by creating experimental colonies of various compositions (six aggressives, three aggressives and three dociles, one aggressive and five dociles, six dociles), maintaining them in a common garden for 3 weeks, and tracking the mass gained by individuals of either phenotype. We found that both the docile and aggressive phenotypes experienced their greatest mass gain in mixed colonies of mostly docile individuals. However, the performance of both phenotypes decreased as the frequency of the aggressive phenotype increased. Nearly identical patterns of phenotype-specific frequency dependence were recovered in all three species. Naturally occurring colonies of these spiders exhibit mixtures dominated by the docile phenotype, suggesting that these spiders may have evolved mechanisms to maintain the compositions that maximize the success of the colony without compromising the expected reproductive output of either phenotype.

Influence of major cardiopulmonary surgery on serum levels of procalcitonin and other inflammatory markers.

Procalcitonin is a marker of significant bacterial infection. With Food and Drug Administration approval of a new high-sensitive procalcitonin assay in the United States, we felt it would be important to assess its normal elevation and time characteristics, as compared to other inflammatory markers in patients undergoing routine cardiac surgery. This is a prospective observational study including consecutive patients after routine cardiac surgery. Blood was sampled preoperatively, immediately postoperatively and daily until discharge or to postoperative day five for measurement of blood markers of infection. Patients were classified into different groups based on the type of surgery (on-pump and off-pump) and progression of recovery (complicated and uncomplicated). Patients after coronary artery bypass grafting off-pump (n=61) had significantly lower mean (0.90 vs 1.13 µg/l, P=0.006) and peak (2.09 vs 2.35 µg/l, P=0.002) procalcitonin levels in the postoperative course compared to patients with either on-pump valve surgery alone, on-pump coronary artery bypass grafting alone (n=28) or valve surgery with coronary artery bypass grafting (n=16). In addition, mean and peak procalcitonin levels were significantly higher (P=0.004 and P=0.002 respectively) in the 60 patients with a complicated course. This study provides insights into 'normal' kinetics of a new high-sensitive procalcitonin assay after different types of cardiac surgery, and in patients with and without a complicated postoperative course. Our results suggest that using a single procalcitonin level to guide antibiotic therapy decisions during the early period after major cardiac surgery may not be useful and that monitoring its kinetic may be the preferred strategy.

The adaptive value of gluttony: predators mediate the life history trade-offs of satiation threshold.

Animals vary greatly in their tendency to consume large meals. Yet, whether or how meal size influences fitness in wild populations is infrequently considered. Using a predator exclusion, mark-recapture experiment, we estimated selection on the amount of food accepted during an ad libitum feeding bout (hereafter termed 'satiation threshold') in the wolf spider Schizocosa ocreata. Individually marked, size-matched females of known satiation threshold were assigned to predator exclusion and predator inclusion treatments and tracked for a 40-day period. We also estimated the narrow-sense heritability of satiation threshold using dam-on-female-offspring regression. In the absence of predation, high satiation threshold was positively associated with larger and faster egg case production. However, these selective advantages were lost when predators were present. We estimated the heritability of satiation threshold to be 0.56. Taken together, our results suggest that satiation threshold can respond to selection and begets a life history trade-off in this system: high satiation threshold individuals tend to produce larger egg cases but also suffer increased susceptibility to predation.

Minimally invasive surgical ablation of atrial fibrillation: the thoracoscopic box lesion approach.

BACKGROUND: Atrial fibrillation is the most common cardiac rhythm disturbance and is associated with increased morbidity and mortality. It is often found in association with structural heart disease; however, lone atrial fibrillation is not uncommon. Potentially, these patients are ideal candidates for a minimally invasive thoracoscopic approach for the surgical treatment of atrial fibrillation. METHODS: From August 2003 through February 2006, 100 drug-resistant symptomatic patients with lone atrial fibrillation underwent thoracoscopic off-pump closed-chest epicardial ablation using the FLEX 10 AFx Microwave Ablation System (Guidant, Indianapolis, IN, USA). There were 66 men (66.0%) and 34 women (34.0%), with a mean age of 60.9 +/- 9.8 (range 37-81) years. Mean duration of atrial fibrillation was 72.4 +/- 79.5 (range 6-480) months. Sixty-four patients (64.0% had paroxysmal, 11 (11.0%) had persistent and 25 (25.0%) had permanent atrial fibrillation. RESULTS: There were no hospital deaths. Postoperative in-hospital complications were minimal. Mean postoperative length of stay was 3.4 +/- 1.7 days. Cumulative follow-up was 2,106.3 (mean 23.1) patient months, with a maximum follow-up of 39.8 months. There were three late deaths (3.0%). In nine patients (9.0%), the thoracoscopic box lesion pulmonary vein isolation operation and subsequent electrophysiological intervention failed, and a Cox-Maze operation was performed. Follow-up was 100% complete, with 42.0% (37 of 88) patients in normal sinus rhythm. Two patients (2.3%) experienced a transient ischemic attack and two (2.3%) a cerebral vascular accident. Twenty-seven patients (30.7%) required electrophysiological intervention post procedure. Ten patients (11.4%) were on amiodarone and 48 (54.5%) were on coumadin at follow-up. CONCLUSION: Totally thoracoscopic surgical ablation for the treatment of atrial fibrillation is technically feasible and presents minimal risk to the patient. Clinical results with the application of microwave energy have been less than satisfactory, with no demonstrated electrical isolation of the pulmonary veins. Moreover, long-term relief from atrial fibrillation has not been achieved.

Left atrial reduction enhances outcomes of modified maze procedure for permanent atrial fibrillation during concomitant mitral surgery.

BACKGROUND: Success of the maze procedure after mitral operations with large left atria and permanent atrial fibrillation remains suboptimal. Current technique variations tend to obscure the decision-making algorithm in these patients. A single energy-source approach for the surgical management of patients with large left atria and permanent atrial fibrillation is presented. METHODS: From January 2003 to July 2005, 71 consecutive drug-resistant patients with permanent atrial fibrillation and left atrial enlargement who required mitral valve surgery underwent aggressive left atrial reduction combined with left-sided only irrigated radiofrequency unipolar maze. Left atrial dimensions were measured by transesophageal echo anterior-to-posterior leading edge-to-edge standardized protocol. There were 39 men (54.9%) and 32 women (45.1%), and their mean age was 71.9 +/- 9.5 years. Mean duration of atrial fibrillation was 49.3 +/- 58.0 months. RESULTS: All patients underwent left atrial reduction with identical Cox-maze III pulmonary vein and appendage isolation including mitral annular connection, followed by appendage suture closure. Left atrial size was reduced from 6.7 +/- 1.2 cm to 4.3 +/- 0.6 cm (p = 0.001). Mitral valve repair was performed in 55 patients (76.1%) and replacement in 17 (23.9%). The 30-day mortality was 4.2% (3/71). Postoperative length of stay was 8.8 +/- 5.7 days, with 56 (82.4%) of 68 patients discharged in normal sinus rhythm. P-wave sinus rhythm was 93.8% between 7 and 12 months and 92.0% for patients with 1 year or more of follow-up. CONCLUSIONS: Left atrial reduction combined with a left atrial only single energy-source radiofrequency maze procedure is an effective treatment for patients with permanent atrial fibrillation undergoing concomitant mitral operations.

Totally endoscopic ablation of lone atrial fibrillation: initial clinical experience.

BACKGROUND: Atrial fibrillation is the most common form of arrhythmia leading to hospital admission. Over 2.2 million Americans are affected by atrial fibrillation and approximately 160,000 new cases are identified annually. As the population continues to age, the number of patients will increase. AF is an incremental risk factor for death and stroke, and consumes billions of dollars in health care expenditures. METHODS: Between August 2003 and October 2004, 50 drug-resistant, symptomatic atrial fibrillation patients underwent thoracoscopic or robotic-assisted off-pump epicardial microwave ablation with the FLEX 10 device (Guidant, Indianapolis, IN). There were 35 men (70.0%) and 15 women (30.0%), mean age 59.1 years +/- 10.0 (range, 37-75 years). Mean duration of atrial fibrillation was 73.5 months +/- 82.3 (range, 5-480 months). Thirty-three patients (66.0%) had intermittent atrial fibrillation and 17 (34.0%) continuous. Intermittent patients had pulmonary vein isolation whereas continuous patients had additional right and left atrial lesions performed. Forty-six patients (92.0%) had endoscopic stapling of the left atrial appendage. RESULTS: There were no hospital deaths. Postoperative in-hospital complications were minimal with 2 patients (4.0%) experiencing diaphragmatic dysfunction. No patient required a permanent pacemaker implant. Mean postoperative length of stay was 3.7 +/- 2.2 days. Cumulative follow-up was 335.8 patient months, mean 7.6 months (range, 2.0-15.9 months). There was 1 late death (2.0%). In 5 patients (10.0%) the MicroMaze operation and subsequent electrophysiology intervention failed and a Cox-Maze III operation was performed. Follow-up was 100% complete with 79.5% (35 of 44) patients in normal sinus rhythm. CONCLUSIONS: Totally endoscopic closed-chest microwave ablation for treatment of intermittent and continuous atrial fibrillation is technically feasible and presents minimal risk to the patient. Initial results are impressive and demonstrate an enhanced quality of life and freedom from atrial fibrillation in drug-resistant symptomatic patients.

Aortic aneurysm repair is associated with a lower inflammatory response compared with surgery for inflammatory bowel disease.

BACKGROUND: Since the plasma cytokine profile reflects the body's inflammatory response to injury, this study was designed to prospectively observe the plasma cytokine levels in response to the degree of different sorts of abdominal surgical trauma. METHODS: Plasma levels of TNF-alpha, type I TNF receptor (p55), type II TNF receptor (p75), IL-6, IL-8, IL-10, phospholipase A(2) (PLA(2)), and haptoglobin were measured peri-operatively in patients undergoing bowel resection for inflammatory bowel disease or diverticulitis (IBD) (n = 9), elective repair of abdominal aortic aneurysm (AAA) (n = 9), or laparoscopic cholecystectomy (lap chole) (n = 9). RESULTS: The IBD patients showed a significant (p < 0.05) post-operative elevation in plasma IL-6, p55, p75, and PLA(2) levels, but no significant change in TNF-alpha, IL-8, IL-10 or haptoglobin levels. The AAA patients had a significant post-operative rise in IL-10 levels and a significant decrease in plasma haptoglobin levels, but no significant change of TNF-alpha, IL-6, IL-8, p55, p75, or PLA(2) concentrations. The lap chole patients demonstrated no significant change in any of these parameters. CONCLUSION: These data show that IL-6, IL-10, p55, and p75 are markers to measure the degree of inflammatory stress associated with abdominal operative procedures and demonstrate the relative lack of a cytokine response to laparoscopic cholecystectomy.

Synthesis and SAR of benzamidine factor Xa inhibitors containing a vicinally-substituted heterocyclic core.

The selective inhibition of coagulation factor Xa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe highly potent benzamidine factor Xa inhibitors based on a vicinally-substituted heterocyclic core.

Interleukin-10 appearance following thoraco-abdominal and abdominal aortic aneurysm repair is associated with the duration of visceral ischaemia.

OBJECTIVES: to evaluate the plasma IL-10 levels during elective operative repair of thoraco-abdominal and abdominal aortic aneurysm repair. To study whether IL-10 plasma levels are associated with the duration of cross-clamping (ischaemia) and clinical outcome. MATERIALS: fifteen consecutive patients undergoing surgery for TAAA and 10 consecutive patients undergoing surgical repair of AAA were included. METHODS: plasma concentrations of IL-10 were measured by ELISA technique. Clinical outcome of the TAAA patients was prospectively analysed. RESULTS: during aortic clamping IL-10 was produced in both populations. The plasma IL-10 peak (934+/-172 pg/ml) of the TAAA group was seen at 4 h after declamping and remained detectable after 48 h. The plasma IL-10 peak (212+/-32 pg/ml) of the AAA group was seen 30 min after declamping and fell to undetectable levels by 24 h. These data show that the peak IL-10 plasma levels in TAAA repair are significantly (p<0.05) higher compared to the peak IL-10 plasma levels as seen during AAA repair. A positive correlation was seen between cross-clamping and peak plasma IL-10 and organ dysfunction. CONCLUSIONS: IL-10 plasma concentrations appear higher, later and are longer detectable in patients undergoing TAAA. Correlations were seen with duration of cross-clamping and MSOD.

Identifying patients "at risk" for alcohol withdrawal syndrome and a treatment protocol.

Alcohol abuse and alcohol dependence are common problems. It is estimated that more than 10 million Americans have problems with alcohol dependence that adversely affect their lives and the lives of their families. Many of these patients, if hospitalized, have the potential to experience symptoms of alcohol withdrawal. Major alcohol withdrawal symptoms may include seizures and the development of delirium tremens. Obtaining an alcohol consumption history is a critical component to identifying patients at risk and determining the appropriate treatment plan for potential alcohol withdrawal. A protocol was established for identifying and treating patients at risk for alcohol withdrawal. The initiation of the treatment protocol is history- and symptom-based; treatment is symptom-triggered on the basis of frequent objective assessments. The purpose of the protocol is to prevent and control withdrawal symptoms without heavily sedating or hindering a patients' neurological assessment.

An investigation of current models of second language speech perception: the case of Japanese adults' perception of English consonants.

This study reports the results of two experiments with native speakers of Japanese. In experiment 1, near-monolingual Japanese listeners participated in a cross-language mapping experiment in which they identified English and Japanese consonants in terms of a Japanese category, then rated the identifications for goodness-of-fit to that Japanese category. Experiment 2 used the same set of stimuli in a categorial discrimination test. Three groups of Japanese speakers varying in English-language experience, and one group of native English speakers participated. Contrast pairs composed of two English consonants, two Japanese consonants, and one English and one Japanese consonant were tested. The results indicated that the perceived phonetic distance of second language (L2) consonants from the closest first language (L1) consonant predicted the discrimination of L2 sounds. In addition, this study investigated the role of experience in learning sounds in a second language. Some of the consonant contrasts tested showed evidence of learning (i.e., significantly higher scores for the experienced than the relatively inexperienced Japanese groups). The perceived phonetic distance of L1 and L2 sounds was found to predict learning effects in discrimination of L1 and L2 sounds in some cases. The results are discussed in terms of models of cross-language speech perception and L2 phonetic learning.

Isoxazolines and isoxazoles as factor Xa inhibitors.

3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis.

Acute exposure to caffeine selectively disrupts context conditioning in rats.

RATIONALE AND OBJECTIVE: Acute caffeine administration has both beneficial and adverse effects on learning and memory; however, the brain regions underlying these effects remain unclear. Several experiments were conducted to examine the effects of acutely administered caffeine on the acquisition and expression of hippocampal-dependent and hippocampal-independent forms of conditioned fear. METHODS: In the first experiment, caffeine (10, 20, or 30 mg/kg; IP) or vehicle was administered to rats 15 min prior to classical fear conditioning, which consisted of ten tone-shock pairings. Freezing to the conditioning context was measured 24 h later, whereas tone-elicited fear was measured 48 h later. A second experiment examined possible state-dependent effects of caffeine by administering caffeine (30 mg/kg) or vehicle 15 min before conditioning and before testing. RESULTS: Pretreatment of acute caffeine severely impaired the acquisition of context conditioning, a hippocampal-dependent task. Tone conditioning, a hippocampal-independent task, was only modestly and non-significantly affected by caffeine (4-21% suppression compared with controls). The disruption of context conditioning was dose-dependent: 10 mg/kg had little effect on context or tone conditioning, whereas doses of 20 and 30 mg/kg caffeine severely disrupted context conditioning (73-87% suppression). In two subsequent experiments, it was found that caffeine's selective disruption of context conditioning could not be attributed to the fact that it is a weaker form of learning than tone conditioning or to state-dependent learning. CONCLUSIONS: Considered together, these results suggest that acute administration of caffeine may preferentially disrupt the acquisition of hippocampal-dependent learning, including context conditioning.

Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1.

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.

Pyrazoles, 1,2,4-triazoles, and tetrazoles as surrogates for cis-amide bonds in boronate ester thrombin inhibitors.

Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.

Rational design of boropeptide thrombin inhibitors: beta, beta-dialkyl-phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile.

The potent boropeptide thrombin inhibitor DuP 714 caused side effects in laboratory animals that appear to be related to its ability to inhibit complement factor I, thereby activating the complement cascade. Using X-ray crystal structure information, we have designed compounds that have greater selectivity for thrombin over factor I and that have reduced tendency to produce these side effects.