Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy

Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V(1393)I, K(1584)E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V(1393)I) and TRPM6(K(1584)E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T(1391)) and TRPM6(S(1583)). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V(1393)I) and TRPM6(K(1584)E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V(1393)I) and TRPM6(K(1584)E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.

Continuous apple consumption induces oral tolerance in birch-pollen-associated apple allergy

Patients with birch pollen allergy (major allergen: Bet v 1) have often an associated oral allergy syndrome (OAS) to apple, which contains the cross-reactive allergen Mal d 1. As successful birch pollen immunotherapy does not consistently improve apple related OAS symptoms, we evaluated whether regular apple consumption has an effect on OAS and immune parameters of Mal d 1 or Bet v 1 allergy.

More accurate component alignment in navigated total knee arthroplasty has no clinical benefit at 5-year follow-up

Computer navigation in total knee arthroplasty is somewhat controversial. We have previously shown that femoral component positioning is more accurate with computed navigation than with conventional implantation techniques, but the clinical impact of this is unknown. We now report the 5-year outcome of our previously reported 2-year outcome study.

Tolerance of intravenous methylprednisolone for relapse treatment in demyelinating CNS disease

In Switzerland, the first course of intravenous steroids for treatment of episodes of demyelinating CNS disease is usually administered in an inpatient setting. We prospectively evaluated short term tolerance of treatment with special emphasis on sleep quality.

Tolerance and Critical Thinking

Post-soviet countries are in the process of transformation from a totalitarian order to a democratic one, a transformation which is impossible without a profound shift in people's way of thinking. The group set themselves the task of determining the essence of this shift. Using a multidisciplinary approach, they looked at concrete ways of overcoming the totalitarian mentality and forming that necessary for an open democratic society. They studied the contemporary conceptions of tolerance and critical thinking and looked for new foundations of criticism, especially in hermeneutics. They then sought to substantiate the complementary relation between tolerance and criticism in the democratic way of thinking and to prepare a a syllabus for teaching on the subject in Ukrainian higher education. In a philosophical exploration of tolerance they began with relgious tolerance as its first and most important form. Political and social interests often lay at the foundations of religious intolerance and this implicitly comprised the transition to religious tolerance when conditions changed. Early polytheism was more or less indifferent to dogmatic deviations but monotheism is intolerant of heresies. The damage wrought by the religious wars of the Reformations transformed tolerance into a value. They did not create religious tolerance but forced its recognition as a positive phenomenon. With the weakening of religious institutions in the modern era, the purely political nature of many conflicts became evident and this stimulated the extrapolation of tolerance into secular life. Each historical era has certain acts and operations which may be interpreted as tolerant and these can be classified as to whether or not they are based on the conscious following of the principle of tolerance. This criterion requires the separation of the phenomenon of tolerance from its concept and from tolerance as a value. Only the conjunction of a concept of tolerance with a recognition of its value can transform it into a principle dictating a norm of conscious behaviour. The analysis of the contemporary conception of tolerance focused on the diversity of the concept and concluded that the notions used cannot be combined in the framework of a single more or less simple classification, as the distinctions between them are stimulated by the complexity of the realty considered and the variety of its manifestations. Notions considered in relation to tolerance included pluralism, respect and particular-universal. The rationale of tolerance was also investigated and the group felt that any substantiation of the principle of tolerance must take into account human beings' desire for knowledge. Before respecting or being tolerant of another person different from myself, I should first know where the difference lies, so knowledge is a necessary condition of tolerance.The traditional division of truth into scientific (objective and unique) and religious, moral, political (subjective and so multiple) intensifies the problem of the relationship between truth and tolerance. Science was long seen as a field of "natural" intolerance whereas the validity of tolerance was accepted in other intellectual fields. As tolerance eemrges when there is difference and opposition, it is essentially linked with rivaly and there is a a growing recognition today that unlimited rivalry is neither able to direct the process of development nor to act as creative matter. Social and economic reality has led to rivalry being regulated by the state and a natural requirement of this is to associate tolerance with a special "purified" form of rivalry, an acceptance of the actiivity of different subjects and a specification of the norms of their competition. Tolerance and rivalry should therefore be subordinate to a degree of discipline and the group point out that discipline, including self-discipline, is a regulator of the balance between them. Two problematic aspects of tolerance were identified: why something traditionally supposed to have no positive content has become a human activity today, and whether tolerance has full-scale cultural significance. The resolution of these questions requires a revision of the phenomenon and conception of tolerance to clarify its immanent positive content. This involved an investigation of the contemporary concept of tolerance and of the epistemological foundations of a negative solution of tolerance in Greek thought. An original soution to the problem of the extrapolation of tolerance to scientific knowledge was proposed based on the Duhem-Quine theses and conceptiion of background knowledge. In this way tolerance as a principle of mutual relations between different scientific positions gains an essential epistemological rationale and so an important argument for its own universal status. The group then went on to consider the ontological foundations for a positive solution of this problem, beginning with the work of Poincare and Reichenbach. The next aspect considered was the conceptual foundations of critical thinking, looking at the ideas of Karl Popper and St. Augustine and at the problem of the demarcation line between reasonable criticism and apologetic reasoning. Dogmatic and critical thinking in a political context were also considered, before an investigation of critical thinking's foundations. As logic is essential to critical thinking, the state of this discipline in Ukrainian and Russian higher education was assessed, together with the limits of formal-logical grounds for criticism, the role of informal logical as a basis for critical thinking today, dialectical logic as a foundation for critical thinking and the universality of the contemporary demand for criticism. The search for new foundations of critical thinking covered deconstructivism and critical hermeneutics, including the problem of the author. The relationship between tolerance and criticism was traced from the ancient world, both eastern and Greek, through the transitional community of the Renaissance to the industrial community (Locke and Mill) and the evolution of this relationship today when these are viewed not as moral virtues but as ordinary norms. Tolerance and criticism were discussed as complementary manifestations of human freedom. If the completeness of freedom were accepted it would be impossible to avoid recognition of the natural and legal nature of these manifestations and the group argue that critical tolerance is able to avoid dismissing such negative phenomena as the degradation of taste and manner, pornography, etc. On the basis of their work, the group drew up the syllabus of a course in "Logic with Elements of Critical Thinking, and of a special course on the "Problem of Tolerance".

High accuracy alignment facility for the receiver and transmitter of the BepiColombo Laser Altimeter

The accurate co-alignment of the transmitter to the receiver of the BepiColombo Laser Altimeter is a challenging task for which an original alignment concept had to be developed. We present here the design, construction and testing of a large collimator facility built to fulfill the tight alignment requirements. We describe in detail the solution found to attenuate the high energy of the instrument laser transmitter by an original beam splitting pentaprism group. We list the different steps of the calibration of the alignment facility and estimate the errors made at each of these steps. We finally prove that the current facility is ready for the alignment of the flight instrument. Its angular accuracy is 23 μrad.

Safety and exercise tolerance of acute high altitude exposure (3454 m) among patients with coronary artery disease

OBJECTIVES: To assess the safety and cardiopulmonary adaptation to high altitude exposure among patients with coronary artery disease. METHODS: 22 patients (20 men and 2 women), mean age 57 (SD 7) years, underwent a maximal, symptom limited exercise stress test in Bern, Switzerland (540 m) and after a rapid ascent to the Jungfraujoch (3454 m). The study population comprised 15 patients after ST elevation myocardial infarction and 7 after a non-ST elevation myocardial infarction 12 (SD 4) months after the acute event. All patients were revascularised either by percutaneous coronary angioplasty (n = 15) or by coronary artery bypass surgery (n = 7). Ejection fraction was 60 (SD 8)%. beta blocking agents were withheld for five days before exercise testing. RESULTS: At 3454 m, peak oxygen uptake decreased by 19% (p < 0.001), maximum work capacity by 15% (p < 0.001) and exercise time by 16% (p < 0.001); heart rate, ventilation and lactate were significantly higher at every level of exercise, except at maximum exertion. No ECG signs of myocardial ischaemia or significant arrhythmias were noted. CONCLUSIONS: Although oxygen demand and lactate concentrations are higher during exercise at high altitude, a rapid ascent and submaximal exercise can be considered safe at an altitude of 3454 m for low risk patients six months after revascularisation for an acute coronary event and a normal exercise stress test at low altitude.