Effects of Epistasis and Pleiotropy on Fitness Landscapes

The factors that influence genetic architecture shape the structure of the fitness landscape, and therefore play a large role in the evolutionary dynamics. Here the NK model is used to investigate how epistasis and pleiotropy -- key components of genetic architecture -- affect the structure of the fitness landscape, and how they affect the ability of evolving populations to adapt despite the difficulty of crossing valleys present in rugged landscapes. Populations are seen to make use of epistatic interactions and pleiotropy to attain higher fitness, and are not inhibited by the fact that valleys have to be crossed to reach peaks of higher fitness.Comment: 10 pages, 6 figures. To appear in "Origin of Life and Evolutionary Mechanisms" (P. Pontarotti, ed.). Evolutionary Biology: 16th Meeting 2012, Springer-Verla

Tamsulosin-induced severe hypotension during general anesthesia: a case report.

Introduction: Tamsulosin, a selective alpha1-adrenergic receptor (alpha1-AR) antagonist, is a widely prescribed first-line agent for benign prostatic hypertrophy (BPH). Its interaction with anesthetic agents has not been described. Case Presentation: We report the case of 54-year-old Asian man undergoing elective left thyroid lobectomy. The only medication the Patient was taking was tamsulosin 0.4 mg for the past year for BPH. He developed persistent hypotension during the maintenance phase of anesthesia while receiving oxygen, nitrous oxide and 1% isoflurane. The hypotension could have been attributable to a possible interaction between inhalational anesthetic and tamsulosin. Conclusion: Vigilance for unexpected hypotension is important in surgical Patients who are treated with selective alpha1-AR blockers. If hypotension occurs, vasopressors that act directly on adrenergic receptors could be more effective

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease has two types, the cardiac form and the digestive form; some patients have symptoms of both. How the parasite causes digestive disease is poorly understood. It is known that damage to the gut’s nervous system is an important factor, but it has been unclear exactly where and when this damage occurs during the course of an infection and also why only a subset of infected people suffer from this outcome. We studied infections in mice and found certain combinations of strains of parasites and mice that exhibited symptoms similar to human digestive Chagas patients, including a problem with peristalsis that localised specifically to the colon. Using parasites that were genetically engineered to emit both bioluminescent and fluorescent light, we tracked infections over time and were able to analyse rare infected cells deep within the muscle tissue of the wall of the colon. We found evidence of damaged neurons in the same location as these infection foci over 6 months after initial infection. Our results show that digestive Chagas disease probably develops as a result of chronic infection and inflammation, which potentially changes approaches to treatment

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution

Infections with Trypanosoma cruzi are usually lifelong despite generating a strong adaptive immune response. Identifying the sites of parasite persistence is therefore crucial to understanding how T. cruzi avoids immune-mediated destruction. However, this is a major technical challenge, because the parasite burden during chronic infections is extremely low. Here, we describe an integrated approach involving comprehensive tissue processing, ex vivo imaging, and confocal microscopy, which allowed us to visualize infected host cells in murine tissue with exquisite sensitivity. Using bioluminescence-guided tissue sampling, with a detection level of 200 parasites, which we term mega-nests. In contrast, during the acute stage, when the total parasite burden is considerably higher and many cells are infected, nests containing >50 parasites are rarely found. In C3H/HeN mice, but not BALB/c mice, we identified skeletal muscle as a major site of persistence during the chronic stage, with most parasites being found in large mega-nests within the muscle fibers. Finally, we report that parasites are also frequently found in the skin during chronic murine infections, often in multiple infection foci. In addition to being a site of parasite persistence, this anatomical reservoir could play an important role in insect-mediated transmission and have implications for drug development.IMPORTANCETrypanosoma cruzi causes Chagas disease, the most important parasitic infection in Latin America. Major pathologies include severe damage to the heart and digestive tract, although symptoms do not usually appear until decades after infection. Research has been hampered by the complex nature of the disease and technical difficulties in locating the extremely low number of parasites. Here, using highly sensitive imaging technology, we reveal the sites of parasite persistence during chronic-stage infections of experimental mice at single-cell resolution. We show that parasites are frequently located in smooth muscle cells in the circular muscle layer of the colon and that skeletal muscle cells and the skin can also be important reservoirs. This information provides a framework for investigating how the parasite is able to survive as a lifelong infection, despite a vigorous immune response. It also informs drug development strategies by identifying tissue sites that must be accessed to achieve a curative outcome

The White Nipple Sign: Please Do Not Disturb

Blood spurting or oozing from a varix confirms the diagnosis of variceal hemorrhage. In most cases of variceal hemorrhage, however, the bleeding has ceased by the time endoscopy is performed. Endoscopists rely on identification of stigmata of recent hemorrhage to determine whether varices are the cause of bleeding and to predict the likelihood of rebleeding. Most of the attention has focused on red color signs, such as red wale markings, described by Beppu et al. [Gastrointest Endosc 1981;27:213-218] and well known to endoscopists. Here we describe our experience with a less recognized stigma of variceal hemorrhage known as the ‘white nipple sign’, which resulted in active hemorrhage when manipulated

Are British Muslims alienated from mainstream politics by Islamophobia and British foreign policy?

This paper uses the 2010 Ethnic Minority British Election Study to look at the political attitudes of Muslims in Britain. It tests the relationship between political alienation and political participation on the one hand, and Islamophobia and disapproval of British military involvement in Afghanistan on the other. The principal findings are that perceptions of Islamophobia are linked to greater political alienation, to a greater likelihood of non-electoral participation and to a lower likelihood of voting among Muslims. Likewise, disapproval of the war in Afghanistan is associated with greater political alienation and a greater likelihood of some types of non-electoral participation. There is strong evidence that British Muslims are more likely to interpret discrimination they experience as motivated by their religion and that they perceive more prejudice at the group level. These findings have two theoretical implications. First, they support the theory that non-electoral participation is motivated by dissatisfaction with the party political system. Second, they suggest that perceptions of sociotropic discrimination (for minorities) and a rare salient political issue in which all parties are in opposition to most voters can lead to negative affect towards the political system and stimulate non-electoral participation at the expense of voting. </jats:p

Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition

BACKGROUND: Over the past several years our research group has taken a systematic, comprehensive approach to determining the effects on body function (hormonal and non-hormonal) of varying the amounts and types of proteins, carbohydrates and fats in the diet. We have been particularly interested in the dietary management of type 2 diabetes. Our objective has been to develop a diet for people with type 2 diabetes that does not require weight loss, oral agents, or insulin, but that still controls the blood glucose concentration. Our overall goal is to enable the person with type 2 diabetes to control their blood glucose by adjustment in the composition rather than the amount of food in their diet. METHODS: This paper is a brief summary and review of our recent diet-related research, and the rationale used in the development of diets that potentially are useful in the treatment of diabetes. RESULTS: We determined that, of the carbohydrates present in the diet, absorbed glucose is largely responsible for the food-induced increase in blood glucose concentration. We also determined that dietary protein increases insulin secretion and lowers blood glucose. Fat does not significantly affect blood glucose, but can affect insulin secretion and modify the absorption of carbohydrates. Based on these data, we tested the efficacy of diets with various protein:carbohydrate:fat ratios for 5 weeks on blood glucose control in people with untreated type 2 diabetes. The results were compared to those obtained in the same subjects after 5 weeks on a control diet with a protein:carbohydrate:fat ratio of 15:55:30. A 30:40:30 ratio diet resulted in a moderate but significant decrease in 24-hour integrated glucose area and % total glycohemoglobin (%tGHb). A 30:20:50 ratio diet resulted in a 38% decrease in 24-hour glucose area, a reduction in fasting glucose to near normal and a decrease in %tGHb from 9.8% to 7.6%. The response to a 30:30:40 ratio diet was similar. CONCLUSION: Altering the diet composition could be a patient-empowering method of improving the hyperglycemia of type 2 diabetes without weight loss or pharmacologic intervention

Daily sperm production and evaluation of morphological reproductive parameters of Murrah buffaloes in an extensive breeding system

The development of male sexual maturity varies among buffaloes. The Murrah buffalo is considered the most important and efficient milk and fat producer, but aspects of its reproductive biology are still unknown. The present study aimed to evaluate the daily sperm production (DSP) and spermatogenesis in developing Murrah buffalo bulls by evaluation of the seminiferous tubules, testicular morphometry and using light microscopy and scanning electron microscopy. The testes of Murrah buffalo bulls at 18 mo was immature and at 24 mo could still be considered an average-efficiency breed based on their DSP. At 24 mo, the DSP rate was 0.97 billion sperm per testis and 13 million sperm per gram of testis. However, the animals had superior morphometric parameters compared with those of other livestock animals, except for the seminiferous tubule volume and diameter, which were inferior. In conclusion, our data support former views that the testes of the Murrah breed does not reach sexual maturity before 2 y of age and that important developmental steps occur later than Murrah crossbreeds from Brazil

Costs and Outcomes of Increasing Access to Bariatric Surgery: Cohort Study and Cost-Effectiveness Analysis Using Electronic Health Records

Objectives: To estimate costs and outcomes of increasing access to bariatric surgery in obese adults and in population subgroups of age, sex, deprivation, comorbidity, and obesity category. Methods: A cohort study was conducted using primary care electronic health records, with linked hospital utilization data, for 3,045 participants who underwent bariatric surgery and 247,537 participants who did not undergo bariatric surgery. Epidemiological analyses informed a probabilistic Markov model to compare bariatric surgery, including equal proportions with adjustable gastric banding, gastric bypass, and sleeve gastrectomy, with standard nonsurgical management of obesity. Outcomes were quality-adjusted life-years (QALYs) and net monetary benefits at a threshold of £30,000 per QALY. Results: In a UK population of 250,000 adults, there may be 7,163 people with morbid obesity including 1,406 with diabetes. The immediate cost of 1,000 bariatric surgical procedures is £9.16 million, with incremental discounted lifetime health care costs of £15.26 million (95% confidence interval £15.18–£15.36 million). Patient-years with diabetes mellitus will decrease by 8,320 (range 8,123–8,502). Incremental QALYs will increase by 2,142 (range 2,032–2,256). The estimated cost per QALY gained is £7,129 (range £6,775–£7,506). Net monetary benefits will be £49.02 million (range £45.72–£52.41 million). Estimates are similar for subgroups of age, sex, and deprivation. Bariatric surgery remains cost-effective if the procedure is twice as costly, or if intervention effect declines over time. Conclusions: Diverse obese individuals may benefit from bariatric surgery at acceptable cost. Bariatric surgery is not cost-saving, but increased health care costs are exceeded by health benefits to obese individuals