Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men

Aims/hypothesis Type 1 diabetic subjects are at increased risk of cardiovascular disease and exhibit multiple qualitative abnormalities of apolipoprotein (apo) B100-containing lipoproteins. This stable isotope kinetic experiment was designed to study whether these abnormalities are associated with changes in the synthesis and fractional catabolic rates of VLDL-, IDL- and LDL-apoB100.Methods Using a bolus followed by a 16-h constant infusion of ¹³C-leucine, we performed a kinetic study in eight men with type 1 diabetes treated with a continuous subcutaneous insulin infusion administered by an external pump and in seven healthy men, in the fed state.Results The mean HbA₁c level in the type 1 diabetic patients was 8.00±1.48%. Plasma triglyceride, and total, LDL and HDL cholesterol levels were similar in patients and control subjects. VLDL were less triglyceride rich in type 1 diabetic patients than in control subjects (VLDL triglyceride : apoB 6.91±0.81 vs 8.29±1.24 mmol/g, p=0.05). Conversely, the IDL and LDL of the type 1 diabetic patients contained relatively higher levels of triglycerides (IDL triglycerides : apoB 2.16±0.36 vs 1.57±0.30 mmol/g, p<0.01; LDL triglycerides : apoB 0.27±0.06 vs 0.16±0.04 mmol/g, p<0.05). The apoB100 pool size, production and fractional catabolic rates in the two groups of subjects were similar for all lipoprotein fractions.Conclusions/interpretation Despite qualitative abnormalities, especially abnormalities of triglyceride content, the metabolism of apoB100-containing lipoproteins is not altered in type 1 diabetic men with fair glycaemic control with continuous subcutaneous insulin infusion. The high risk of atherosclerosis in these patients cannot be explained by kinetic abnormalities of apoB100-containing lipoproteins.     

Novel use of a modified Amplatzer Vascular Plug® to occlude a patent ductus arteriosus in two patients

We describe two cases in which a patent ductus arteriosus (PDA) was successfully occluded percutaneously, using the novel approach of prefilling an Amplatzer Vascular Plug® with embolization coils to decrease the risk of residual shunting through the device. One patient was a small premature neonate, and the other was a child with an aneurismal, tubular PDA with no aortic ampulla. These are situations in which more popular PDA devices such as the Amplatzer Duct Occluder® may be contraindicated. © 2008 Wiley‐Liss, Inc.     

Longitudinal changes in activity patterns, physical capacities, energy expenditure, and body composition in severely obese adolescents during a multidisciplinary weight-reduction program

OBJECTIVE: To determine the longitudinal changes in body composition, physical capacities, and time and energy expenditure (EE) devoted to various activities in the course of a 9-month weight-reduction period. DESIGN: Longitudinal, clinical intervention including lifestyle education, moderate energy restriction, progressive training, and psychological follow-up. SUBJECTS: A total of 27 (13 boys and 14 girls) severely obese adolescents (mean BMI: 33.9 kg/m2; 41.5% fat mass (FM)), aged 12-16 y. MEASUREMENTS: Before the beginning and after the weight-reduction program, body composition was assessed by dual-energy X-ray absorptiometry (DXA), physical capacities by multistage treadmill test, and EE both by whole-body calorimetry and in free-living conditions using the heart rate-recording method. During 8 months of the weight-reduction period, type and duration of each activity were recorded using a daily controlled activity diary. RESULTS: One boy resigned after 5 months. Body weight (BW) and FM decreased (-19 and -42%, respectively, P<0.001) both in boys and in girls, but fat-free mass (FFM) decreased only in girls (-6%, P<0.001). VO2max (l/min) did not vary significantly, but strength and fitness were improved (P<0.001). Time and EE spent at sedentary activities decreased significantly (P<0.001) to the benefit of moderate (recreational) activities and total physical activities (P<0.001) at the institution during the weekdays, and at home during the weekends and holidays. CONCLUSION: The great BW and FM losses, preservation of FFM, and improvement of physical capacities of obese adolescents obtained under experimental conditions were associated with increases in leisure physical activities in free-living conditions at the expense of sleep and sedentary activities.     

Tumor‐induced myeloid‐derived suppressor cell subsets exert either inhibitory or stimulatory effects on distinct CD8+ T‐cell activation events

Tumor growth coincides with an accumulation of myeloid‐derived suppressor cells (MDSCs), which exert immune suppression and which consist of two main subpopulations, known as monocytic (MO) CD11b⁺CD115⁺Ly6G^?Ly6C^high MDSCs and granulocytic CD11b⁺CD115^?Ly6G⁺Ly6C^int polymorphonuclear (PMN)‐MDSCs. However, whether these distinct MDSC subsets hamper all aspects of early CD8⁺ T‐cell activation — including cytokine production, surface marker expression, survival, and cytotoxicity — is currently unclear. Here, employing an in vitro coculture system, we demonstrate that splenic MDSC subsets suppress antigen‐driven CD8⁺ T‐cell proliferation, but differ in their dependency on IFN‐γ, STAT‐1, IRF‐1, and NO to do so. Moreover, MO‐MDSC and PMN‐MDSCs diminish IL‐2 levels, but only MO‐MDSCs affect IL‐2Rα (CD25) expression and STAT‐5 signaling. Unexpectedly, however, both MDSC populations stimulate IFN‐γ production by CD8⁺ T cells on a per cell basis, illustrating that some T‐cell activation characteristics are actually stimulated by MDSCs. Conversely, MO‐MDSCs counteract the activation‐induced change in CD44, CD62L, CD162, and granzyme B expression, while promoting CD69 and Fas upregulation. Together, these effects result in an altered CD8⁺ T‐cell adhesiveness to the extracellular matrix and selectins, sensitivity to FasL‐mediated apoptosis, and cytotoxicity. Hence, MDSCs intricately influence different CD8⁺ T‐cell activation events in vitro, whereby some parameters are suppressed while others are stimulated.     

What's wrong with fear conditioning?

Fear conditioning is one of the prime paradigms of behavioural neuroscience and a source of tremendous insight in the fundamentals of learning and memory and the psychology and neurobiology of emotion. It is also widely regarded as a model for the pathogenesis of anxiety disorders in a diathesis-stress model of psychopathology. Starting from the apparent paradox between the adaptive nature of fear conditioning and the dysfunctional nature of pathological anxiety, we present a critique of the human fear conditioning paradigm as an experimental model for psychopathology. We discuss the potential benefits of expanding the human fear conditioning paradigm by (1) including action tendencies as an important index of fear and (2) paying more attention to “weak” (i.e., ambiguous) rather than “strong” fear learning situations (Lissek et al., 2006), such as contained in selective learning procedures. We present preliminary data that illustrate these ideas and discuss the importance of response systems divergence in understanding individual differences in vulnerability for the development of pathological anxiety.     

The Hippo pathway: Horizons for innovative treatments of peripheral nerve diseases

Initially identified in Drosophila, the Hippo signaling pathway regulates how cells respond to their environment by controlling proliferation, migration and differentiation. Many recent studies have focused on characterizing Hippo pathway function and regulation in mammalian cells. Here, we present a brief overview of the major components of the Hippo pathway, as well as their regulation and function. We comprehensively review the studies that have contributed to our understanding of the Hippo pathway in the function of the peripheral nervous system and in peripheral nerve diseases. Finally, we discuss innovative approaches that aim to modulate Hippo pathway components in diseases of the peripheral nervous system.     

Effect of build orientation on the manufacturing process and the properties of stereolithographic dental ceramics for crown frameworks

Statement of problemStereolithography (SLA) ceramic crown frameworks are suitable for clinical use, but the impact of SLA build orientation has not been identified.PurposeThe purpose of this in vitro study was to investigate the effect of 3 build orientations on the physical and mechanical properties and the microstructure of SLA alumina dental ceramics.Material and methodsThe physical and mechanical properties and microstructures of 3 different oriented SLA alumina ceramics (ZX, ZY, and XY) were evaluated by visual observation, hydrostatic weighing (n=10/group), Weibull analyses (n=30/group), scanning electron microscopy, 3-point flexural strength (n=30/group), fracture toughness (indentation, single-edge-V-notched-beam) (n=4/group), and Vickers hardness (n=15/group) testing. The hydrostatic weighing, 3-point flexural strength, fracture toughness, and Vickers hardness testing data were statistically analyzed (α=.05).ResultsThe minimum resting period of slurries between the polymerization of 2 layers was shorter for the ZY- and ZX-oriented specimens and increased with the layer surface. The density and Vickers hardness of the SLA-manufactured specimens were similar for all groups (P>.05). The 95% confidence intervals of the Weibull moduli of the ZX- and ZY-oriented specimens were higher than that of the XY-oriented specimens, with no overlap fraction. The ZY-oriented specimens displayed significantly higher 3-point flexural strength (P<.05) and fracture toughness as evaluated by the single-edge-V-notched-beam method than the ZX-oriented specimens (P<.05). They also displayed significantly higher 3-point flexural strength than the XY-oriented specimens (P<.05). The microstructural analysis showed that the texturing was heterogeneous and that the major axis of the large grains of alumina ran parallel to the orientation of the layers.ConclusionsThe ZY orientation produced a reliable dental ceramic by SLA, with the shortest general manufacturing time and the highest mechanical strength when the layers were perpendicular to the test load surface.