Irregular connexin43 expressed in a rare cardiac hamartoma containing adipose tissue in the crista terminalis

Cardiac hamartomas are very rare and are demarcated masses of enlarged, hypertrophied, mature myocytes and collagen tissue. Cardiac hamartomas are generally circumscribed in the right ventricle or atrium, but not reported in the crista terminalis (CRT). The CRT is crucial in electrophysiology, is related to arrhythmogenesis, and is targeted by radiofrequency catheter procedures. Previous works only described the benign natures of prominent CRT using non-invasive methods. This study describes an unusual cardiac hamartoma originating from the CRT and extending toward the tricuspid valve. Microscopically, this hamartoma comprised dense collagen and adipose tissue, mixed with hypertrophy, but with disarrayed cardiomyocytes. An irregular gap junction, connexin43, was demonstrated in this cardiac hamartoma.     

A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4

Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.     

Neck proprioception compensates for age-related deterioration of vestibular self-motion perception

Vestibular functions are known to show some deterioration with age. Vestibular deterioration is often thought to be compensated for by an increase in neck proprioceptive gain. We studied this presumed compensatory mechanism by measuring psychophysical responses to vestibular (horizontal canal), neck and combined stimuli in 50 healthy human subjects as a function of age (range 15–76 years). After passive horizontal rotations of head and/or trunk (torso) in complete darkness (dominant frequencies 0.05, 0.1, and 0.4 Hz), subjects readjusted a visual target to its remembered prerotational location in space. (1) Vestibular-only stimulus (whole-body rotation); subjects' responses were shifted towards postrotatory body position, this only slightly at 0.4 Hz and pronounced at 0.1 and 0.05 Hz. These errors reflect the known physiological drop of vestibular gain at low rotational frequency. They exhibited a slight but significant increase with age. (2) Neck-only stimulus (trunk rotated, head stationary); the responses showed errors similar to those upon vestibular stimulation (with offset towards postrotatory trunk position) and this again slightly more with increasing age. (3) Vestibular-neck stimulus combination during head rotation on stationary trunk; the errors were close to zero, independent of stimulus frequency and the subjects' age. (4) Opposite stimulus combination (trunk rotated in the same direction as the head, but with double amplitude); the errors were clearly enhanced, essentially reflecting the sum of those with vestibular-only and neck-only stimulation. Taken together, we find a parallel increase in neck- and vestibular-related errors with age, in seeming contrast to previous studies. We explain our and the previous findings by a vestibular-neck interaction model in which two different neck signals are involved. One neck signal is used, in combination with the vestibular signal, for estimating trunk-in-space rotation. It is internally shaped to always match the vestibular signal, so that these two signals cancel each other out when summed during head rotation on stationary trunk. Because of this matching, perceived trunk stationariness during head rotation on the stationary trunk is independent of vestibular deterioration (related to stimulus frequency, age, ototoxic medication, etc.). The other neck proprioceptive signal, coding head-on-trunk rotation, is superimposed on the estimate of trunk-in-space rotation, thereby yielding a notion of head-in-space. This neck signal remains essentially unchanged with vestibular deterioration. Generally, we hold that the transformation of the vestibular signal from the head down to the trunk proceeds further to include the hip and the legs as well as the haptically perceived body support surface; by this, subjects yield a notion of support kinematics in space. As a consequence, spatial orientation is impaired by chronic vestibular deterioration only to the extent that the body support is moving in space, while it is unimpaired (determined by proprioception alone) during body motion with respect to a stationary support. Electronic Publication     

A blood-borne antigen induces rapid T-B cell contact: a potential mechanism for tolerance induction

Understanding the difference between the development of a productive T‐cell response and tolerance is central to discerning how the immune system functions. Intravenous injection of soluble protein is thought to mimic the presentation of self‐serum and orally introduced antigens. It is generally toleragenic. The current view is that this outcome reflects the failure of ‘immunogenic’ dendritic cells to relocate to the T‐cell zone of the secondary lymphoid tissues. Here, using a peptide/I‐E^k tetramer and antibodies to stain splenic sections, we showed that antigen‐specific T cells were activated in the spleen within hours of injection or feeding of protein. The activated T cells were found to be located at the T–B junction, the bridging zone and the B‐cell area, interacting directly with B cells. In addition, B cells gain the ability to present antigen. Our results suggest a way for T cells to be stimulated by blood‐borne antigen presented by naïve B cells, a potential mechanism of tolerance induction.     

The effects of co-culture with human fibroblasts on human embryo development in vitro and implantation

In a human in-vitro fertilization (IVF) programme, the effect of co- culture of embryos with human fibroblasts was evaluated with respect to pregnancy rate and embryo development. Patients were included in the study after giving informed written consent. The IVF treatments were randomly assigned by stratification of both age (<36 versus > or =36 years) and previous IVF attempts (yes versus no). After fertilization was established, the zygotes were transferred to a 4-well dish with or without fibroblasts and cultured for 2 days. On the third day after ovum pick-up (OPU), cell number and quality [5 (good) to 1 (poor)] of the embryos were scored and a maximum of three embryos was transferred. Supernumerary embryos of good quality were cryopreserved. The design of this study was a group sequential trial with the objective of detecting differences between pregnancy rates following IVF with conventional incubation or incubation in co-culture with fibroblasts. This design included one evaluation at half-way data collection. In the study, 148 patients had an OPU, of whom 77 were allocated to the co-culture group. There was no statistically significant difference in pregnancy rate, cell number and embryo quality between the two groups. The ongoing pregnancy rate per embryo transfer was 27% in co-culture and 30% in the conventional culture group. The implantation rates per transferred embryo were 17 and 18% respectively. Using a multivariate logistic regression model for the probability of ongoing pregnancies, the odds ratio of co-culture, adjusted for age and previous IVF attempts, was not statistically significant. In conclusion, co-culture with human fibroblasts does not contribute to an improvement of embryo quality nor to a higher pregnancy rate after IVF in an unselected group of patients.      

Accumulation of arachidonate in triacylglycerols and unesterified fatty acids during ischemia and reflow in the isolated rat heart. Correlation with the loss of contractile function and the development of calcium overload.

Alterations in triacylglycerol and phospholipid metabolism are known to occur during the evolution of myocardial ischemic injury. The purpose of this study was to explore potential relationships between the accumulation of arachidonic acid and other fatty acids, the accumulation of triacylglycerol, and the progression of myocardial injury. Measurements of the fatty acid levels in triacylglycerol, unesterified fatty acids, and calcium content were correlated with myocardial function during ischemia and ischemia with reflow in an isolated perfused rat heart preparation. After 10 minutes of ischemia in this model, myocardial dysfunction was reversible, with recovery of left ventricular +dP/dt to 82.0% +/- 4.8% of control values upon reperfusion. Hearts did not recover with reperfusion after 30 minutes of ischemia and displayed a significant increase in tissue calcium content. A significant, nearly threefold increase in the arachidonic acid content of triacylglycerol was found after 10 minutes of ischemia and continued to increase with longer periods of ischemia and reflow. Other fatty acids also showed increased levels in triacylglycerol. The time course of accumulation of unesterified arachidonic acid paralleled the loss of myocardial function. Levels of free arachidonic acid were (in nanomoles per gram wet weight) 11.1 +/- 2.1 (SEM) for control hearts, 17.3 +/- 1.9 after 10 minutes of ischemia, and 38.4 +/- 2.5 after 30 minutes of ischemia. Increases in other free fatty acids contributed to a significant increase in total free fatty acid accumulation after 30 minutes of ischemia. Thus, the content of arachidonic and other fatty acids in triacylglycerol was found to increase early during ischemia, and a major increase in free arachidonic and other unesterified fatty acids occurred after a longer period of ischemia. These findings are consistent with an initial reincorporation of free fatty acids into triacylglycerol after release from membrane phospholipids, suggesting that membrane fatty acids may be a major source of triacylglycerol that accumulates in ischemic myocardium. In addition, these results suggest that a major increase in free fatty acids during ischemia and ischemia with reflow correlates temporally with the development of severe contractile dysfunction and accumulation of calcium in the heart.