Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease.

The sphingosine-1-phosphate receptor-1 (S1P1) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P1 in intestine using S1P1-eGFP mice, the regulation of S1P1 expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4+CD45RBhi cells, and by crossing a mouse with TNF-driven ileitis with S1P1-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P1 expression. We found that not only T and B cells express S1P1, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P1 expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P1 degradation and retention of Naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P1 expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.

A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder.

This is the first longitudinal twin study examining genetic and environmental contributions to the association between liability to bipolar disorder (BD) and changes over time in global brain volumes, and global and regional measures of cortical surface area, cortical thickness and cortical volume. A total of 50 twins from pairs discordant or concordant for BD (monozygotic: 8 discordant and 3 concordant pairs, and 1 patient and 3 co-twins from incomplete pairs; dizygotic: 6 discordant and 2 concordant pairs, and 1 patient and 7 co-twins from incomplete pairs) underwent magnetic resonance imaging twice. In addition, 57 twins from healthy twin pairs (15 monozygotic and 10 dizygotic pairs, and 4 monozygotic and 3 dizygotic subjects from incomplete pairs) were also scanned twice. Mean follow-up duration for all twins was 7.5 years (standard deviation: 1.5 years). Data were analyzed using structural equation modeling software OpenMx. The liability to BD was not associated with global or regional structural brain changes over time. Although we observed a subtle increase in cerebral white matter in BD patients, this effect disappeared after correction for multiple comparisons. Heritability of brain changes over time was generally low to moderate. Structural brain changes appear to follow similar trajectories in BD patients and healthy controls. Existing brain abnormalities in BD do not appear to progressively change over time, but this requires additional confirmation. Further study with large cohorts is recommended to assess genetic and environmental influences on structural brain abnormalities in BD, while taking into account the influence of lithium on the brain.

Orientation sensitive properties of visually driven neurons in extrastriate area 21a of cat cortex.

Orientation sensitive properties of extrastriate area 21a neurons were investigated. Special attention was paid to the qualitative characteristics of neuron responses to the different orientations of visual stimulus motion across neuron classical receptive fields (CRF). The results of experiments have shown that a group of neurons (31%) in area 21a with specialized responses to moving visual stimuli changed their direction selective (DS) characteristics depending on the orientation of the stimulus movement. Some neurons reveal an abrupt drop of the direction sensitivity index (DI) to certain orientation (58%), and some show significant increase of DI at one of applied orientations of stimulus motion (22%). Detailed investigation of response patterns of non-directional neurons to different orientations of stimulus motion have revealed clear-cut qualitative differences, such as different regularities in the distribution of inter-peak inhibitory intervals in the response pattern in dependence of the orientation of stimulus motion. The investigation of neuron CRF stationary functional organization did not reveal correlations between RF's spatial functional organization, and that of qualitative modulations of neuron response patterns. A suggestion was put forward, that visual information central processing of orientation discrimination is a complex integrative process that includes quantitative as well as qualitative transformations of neuron activity.

Spatial summation processes in the receptive fields of visually driven neurons of the cat's cortical area 21a.

The spatial summation in receptive fields (RF) of single neurons in cat's extrastriate area 21a was investigated as a basic neurophysiological substrate for central integration processing of visual information. The results showed that the majority of investigated neurons changed their response patterns with gradual increase of applied stimulus size. In approximately 82% of cases the suppression of neuron discharges was observed when the length of the moving strip exceeded that of the RF. In some neurons the increased size of the moving stimulus leads to the changes in the RF substructure. Receptive fields of neurons recorded at the same microelectrode penetration depth showed a great variety of RF superpositions distributed in a spatially asymmetric manner. As a result, every single RF consists of multiple sub-regions within the RF, differing from each other by the number of superimposed RF-s (density factor). We suggest that such complex spatial organization of the RF provides the neurophysiological basis for central integration processing of the visual information.

In vivo production of cytokines by bone marrow stromal cells and macrophages from patients with myelodysplastic syndrome.

We studied functional disturbances in hemopoietic microenvironment and cytokine production by stromal sublayer in long-term bone marrow cultures and peripheral blood macrophages from patients with various forms of myelodysplastic syndrome. Production of factors stimulating the growth of normal erythroid and granulocytic precursors by cells of the stromal sublayer from patients with refractory sideroblast anemia and refractory anemia with excess blasts is impaired compared to cells from healthy donors. The medium conditioned by macrophages from patients with chronic myelomonocytic leukemia displayed a higher ability to stimulate the growth of granulocytes and macrophages compared to media conditioned by cells from donors and patients with refractory sideroblast anemia and refractory anemia with excess blasts. Cultured stromal cells and macrophages produced tumor necrosis factor-alpha and interleukin-6. Their content in media conditioned by cells from patients with myelodysplastic syndrome surpassed that in healthy donors. Our results suggest that production of cytokines by stromal microenvironmental cells is impaired in patients with various forms of myelodysplastic syndrome.

Selective nonoperative management in 1,856 patients with abdominal gunshot wounds: should routine laparotomy still be the standard of care?

OBJECTIVE: To evaluate the safety of a policy of selective nonoperative management (SNOM) in patients with abdominal gunshot wounds. SUMMARY BACKGROUND DATA: Selective nonoperative management is practiced extensively in stab wounds and blunt abdominal trauma, but routine laparotomy is still the standard of care in abdominal gunshot wounds. METHODS: The authors reviewed the medical records of 1,856 patients with abdominal gunshot wounds (1,405 anterior, 451 posterior) admitted during an 8-year period in a busy academic level 1 trauma center and managed by SNOM. According to this policy, patients who did not have peritonitis, were hemodynamically stable, and had a reliable clinical examination were observed. RESULTS: Initially, 792 (42%) patients (34% of patients with anterior and 68% with posterior abdominal gunshot wounds) were selected for nonoperative management. During observation 80 (4%) patients developed symptoms and required a delayed laparotomy, which revealed organ injuries requiring repair in 57. Five (0.3%) patients suffered complications potentially related to the delay in laparotomy, which were managed successfully. Seven hundred twelve (38%) patients were successfully managed without an operation. The rate of unnecessary laparotomy was 14% among operated patients (or 9% among all patients). If patients were managed by routine laparotomy, the unnecessary laparotomy rate would have been 47% (39% for anterior and 74% for posterior abdominal gunshot wounds). Compared with patients with unnecessary laparotomy, patients managed without surgery had significantly shorter hospital stays and lower hospital charges. By maintaining a policy of SNOM instead of routine laparotomy, a total of 3,560 hospital days and $9,555,752 in hospital charges were saved over the period of the study. CONCLUSION: Selective nonoperative management is a safe method for managing patients with abdominal gunshot wounds in a level 1 trauma center with an in-house trauma team. It reduces significantly the rate of unnecessary laparotomy and hospital charges.