Intestinal epithelial cell-derived interleukin-7: A mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition

Total parenteral nutrition (TPN), with the absence of enteral nutrition, results in profound changes to both intestinal epithelial cells (EC) as well as the adjacent intraepithelial lymphocyte (IEL) population. Intestinal EC are a rich source of IL-7, a critical factor to support the maintenance of several lymphoid tissues, and TPN results in marked EC changes. On this basis, we hypothesized that TPN would diminish EC-derived IL-7 expression and that this would contribute to the observed changes in the IEL population. Mice received enteral food and intravenous crystalloid solution (control group) or TPN. TPN administration significantly decreased EC-derived IL-7 expression, along with significant changes in IEL phenotype; decreased IEL proliferation; and resulted in a marked decrease in IEL numbers. To better determine the relevance of TPN-related changes in IL-7, TPN mice supplemented with exogenous IL-7 or mice allowed ad libitum feeding and treated with exogenous administration of anti-IL-7 receptor (IL-7R) antibody were also studied. Exogenous IL-7 administration in TPN mice significantly attenuated TPN-associated IEL changes, whereas blocking IL-7R in normal mice resulted in several similar changes in IEL to those observed with TPN. These findings suggest that a decrease in EC-derived IL-7 expression may be a contributing mechanism to account for the observed TPN-associated IEL changes.     

Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis

Background & Aims: Intestinal adaptation in short bowel syndrome (SBS) consists of increased epithelial cell (EC) proliferation as well as apoptosis. Previous microarray analyses of intraepithelial lymphocytes (IEL) gene expression after SBS showed an increased expression of angiotensin converting enzyme (ACE). Because ACE has been shown to promote alveolar EC apoptosis, we examined if IEL-derived ACE plays a role in intestinal EC apoptosis. Methods: Mice underwent either a 70% mid-intestinal resection (SBS group) or a transection (Sham group) and were studied at 7 days. ACE expression was measured, and ACE inhibition (ACE-I, enalaprilat) was used to assess ACE function. Results: IEL-derived ACE was significantly elevated in SBS mice. The addition of an ACE-I to SBS mice resulted in a significant decline in EC apoptosis. To address a possible mechanism, tumor necrosis factor alpha (TNF-α) mRNA expression was measured. TNF-α was significantly increased in SBS mice, and decreased with ACE-I. Interestingly, ACE-I was not able to decrease EC apoptosis in TNF-α knockout mice. Conclusions: This study shows a previously undescribed expression of ACE by IEL. SBS was associated with an increase in IEL-derived ACE. ACE appears to be associated with an up-regulation of intestinal EC apoptosis. ACE-I significantly decreased EC apoptosis.     

Time-frequency analysis of visual evoked potentials for interhemispheric transfer time and proportion in callosal fibers of different diameters

This study is an extension of the experimental research of Nalçac et al., who presented 16 subjects with a reversal of checkerboard pattern as stimuli in the right visual field or left visual field and recorded EEG at O1, O2, P3, and P4. They applied the chosen bandpass filters (4–8, 8–15, 15–20, 20–32 Hz) to the VEPs of subjects and obtained four different components for each VEP. The first aim of this study is to improve the previous report using some methods in time-frequency domain to estimate interhemispheric delays and amplitudes in a time window. Using the improved estimates of interhemispheric delays, the second aim is to estimate the proportion of callosal fibers of different diameters that are activated by visual stimuli by comparing amplitudes of VEPs in different frequency bands. If the relation between frequency components of VEP and delays for callosal fibers of different dimension were reliable, it would give us an opportunity to deal with amplitude of bandpass-filtered VEPs in order to see approximately the proportion of these fibers activated by a certain stimulus. By using frequency-dependent shifts in time and maximizing the cross correlation of direct VEP (DVEP–VEP obtained from contralateral hemisphere)–indirect VEP (IVEP–VEP obtained from ipsilateral hemisphere) pairs in the time-frequency domain, we examined the delay not only at P100 and N160 peaks but along a meaningful time interval as well. Furthermore, by shifting back the IVEP according to the delay estimated at each time window, both the amplitudes and energies of the synchronized DVEP–IVEP pairs were compared at the chosen frequency bands. The percentages of IVEPs at each band was then examined further in conjunction with the distribution of axon diameters in the posterior pole of the CC, questioning the relation between the distributions of the axon diameters and activations at each band. We established an energy definition to express the activation in the fibers. When the energy percentages of IVEPs in theta and alpha were totaled, they were found to be between 76.2% and 81.6%, which is close to the value 74–77% for fibers of 0.4–1 m in diameter obtained from anatomical study of human CC. The sum of energy percentages in the beta1 and beta2 bands was between 20.1% and 24.2%, which probably reflects the proportion of activation of callosal fibers 1–3 m in diameter.     

Comparing unilateral and bilateral upper limb training: The ULTRA-stroke program design

Background  

About 80% of all stroke survivors have an upper limb paresis immediately after stroke, only about a third of whom (30 to 40%) regain some dexterity within six months following conventional treatment programs. Of late, however, two recently developed interventions - constraint-induced movement therapy (CIMT) and bilateral arm training with rhythmic auditory cueing (BATRAC) - have shown promising results in the treatment of upper limb paresis in chronic stroke patients. The ULTRA-stroke (acronym for Upper Limb TRaining After stroke) program was conceived to assess the effectiveness of these interventions in subacute stroke patients and to examine how the observed changes in sensori-motor functioning relate to changes in stroke recovery mechanisms associated with peripheral stiffness, interlimb interactions, and cortical inter- and intrahemispheric networks. The present paper describes the design of this single-blinded randomized clinical trial (RCT), which has recently started and will take several years to complete.     

Decline in intestinal mucosal IL-10 expression and decreased intestinal barrier function in a mouse model of total parenteral nutrition

Loss of intestinal epithelial barrier function (EBF) is a major problem associated with total parenteral nutrition (TPN) administration. We have previously identified intestinal intraepithelial lymphocyte (IEL)-derived interferon-gamma (IFN-gamma) as a contributing factor to this barrier loss. The objective was to determine whether other IEL-derived cytokines may also contribute to intestinal epithelial barrier breakdown. C57BL6J male mice received TPN or enteral nutrition (control) for 7 days. IEL-derived interleukin-10 (IL-10) was then measured. A significant decline in IEL-derived IL-10 expression was seen with TPN administration, a cytokine that has been shown in vitro to maintain tight junction integrity. We hypothesized that this change in IEL-derived IL-10 expression could contribute to TPN-associated barrier loss. An additional group of mice was given exogenous recombinant IL-10. Ussing chamber experiments showed that EBF markedly declined in the TPN group. TPN resulted in a significant decrease of IEL-derived IL-10 expression. The expression of several tight junction molecules also decreased with TPN administration. Exogenous IL-10 administration in TPN mice significantly attenuated the TPN-associated decline in zonula occludens (ZO)-1, E-cadherin, and occludin expression, as well as a loss of intestinal barrier function. TPN administration led to a marked decline in IEL-derived IL-10 expression. This decline was coincident with a loss of intestinal EBF. As the decline was partially attenuated with the administration of exogenous IL-10, our findings suggest that loss of IL-10 may be a contributing mechanism to TPN-associated epithelial barrier loss.