Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause,and short-duration mild hypothermia is a highly effective preventive therapy

In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke. Here, our aims were to determine the importance of edema in ICP elevation after stroke and whether mild hypothermia could prevent the ICP rise. Experimental stroke was performed in rats. ICP was monitored and short-duration mild (35 °C) or moderate (32.5 °C) hypothermia, or normothermia (37 °C) was induced after stroke onset. Edema was measured in three studies, using wet–dry weight calculations, T₂-weighted magnetic resonance imaging, or histology. ICP increased 24 hours after stroke onset in all normothermic animals. Short-duration mild or moderate hypothermia prevented this rise. No correlation was seen between ΔICP and edema or infarct volumes. Calculated rates of edema growth were orders of magnitude less than normal cerebrospinal fluid production rates. These data challenge current concepts and suggest that factors other than cerebral edema are the primary cause of the ICP elevation 24 hours after stroke onset.     

Effect of atrial natriuretic peptide on DOPA potentiation in mice

The effect of rat atrial natriuretic peptide (ANP1-28) on the pargyline-DOPA potentiation test was studied following its administration into the lateral brain ventricle in mice. Thirty minutes after pargyline pretreatment, three doses of ANP (200, 500, or 1,000 ng/mouse) were administered simultaneously with DOPA and animals were then observed for 2 h. ANP in doses of 500 and 1,000 ng markedly enhanced the effect of DOPA. The maximum intensity of the effect was registered 30-45 min following administration of the peptide. The data suggest that ANP might be regarded as a dopaminergic-modulating agent in the CNS.     

Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment

Accumulating evidence indicates an immunosuppressive role of the thymus-derived CD4+ T-cell population constitutively expressing high level of CD25, T regulatory (Treg) cells, in autoimmune diseases. Here we show that the number of Treg cells in the blood is significantly lower in untreated myasthenia gravis patients than in age-matched healthy subjects, whereas it is normal or elevated in patients on immunosuppressive therapy (prednisone frequently associated with azathioprine). Therapeutic thymectomy (Tx) for either the thymoma or non-neoplastic thymic alterations that are often associated with myasthenia gravis provided unique material for studying intrathymic Treg cells and correlating them with their peripheral counterparts. We observed that Tx prevents the increase of Treg cells in the circulation that follows immunosuppressive therapy (particularly evident if the thymus is not neoplastic), indicating that the thymus contributes to Treg-cell normalization. However, thymic Treg cells are not modulated by immunosuppressive therapy and even in thymectomized patients Treg-cell numbers in the blood eventually recover. The present findings suggest that a deficiency in Treg cells favours the development of myasthenia gravis and that their normalization is an important clinical benefit of immunosuppressive therapy. Treg normalization appears to be largely thymus independent and possibly reflects the reported capacity of corticosteroids to promote Treg-cell development.     

Aversion to risk and guilt

Much research has shown that cognitive processes are largely guided by individuals' states of mind (Mancini & Gangemi, 2002a, in press; Smeets, de Jong, & Mayer, 2000). In this paper, we specifically consider a state of mind characterized by guilt for having acted irresponsibly. This state is currently considered the breeding ground for the obsessive–compulsive disorder (Rachman, 2002; Salkovskis & Forrester, 2002). Our aim is to examine the impact of this state of mind on decision under risk. We hypothesize that individuals' choices (risk seeking/risk aversion) depend on how they evaluate themselves, as guilty or as victims of a wrong, and thus on moral values. People who evaluate them‐selves as guilty are expected to show a risk‐averse preference. People who evaluate themselves as victims are expected to show a risk‐seeking preference. In two different experiments, we demonstrated that non‐clinical participants' aversion to risky choices and preference for risky choices vary as a function of their moral role (guilty/victim). As predicted, in both the experiments, participants experienced intolerance for risk, making more riskless choices, in the context of guilt. Thus, aversion to risk‐taking is actually affected by a mental state of guilt. Copyright © 2004 John Wiley & Sons, Ltd.     

MUC18 regulates IL-13-mediated airway inflammatory response

Objective

To evaluate the effects of MUC18 on IL-13-mediated airway inflammatory responses in human airway epithelial cells and in mice.

Materials

Primary normal human tracheobronchial epithelial (HTBE) cells, wild-type (WT) and Muc18 knockout (KO) mice, and mouse tracheal epithelial cells (mTECs) were utilized.

Treatment

Cultured HTBE cells treated with MUC18 siRNA or MUC18 expressing lentivirus were incubated with IL-13 (10 ng/mL) for 24 h. Mice were intranasally instilled with 500 ng of IL-13 for 3 days. mTECs were treated with IL-13 (10 ng/mL) for 3 days.

Methods

PCR was used to measure mRNA expression. Western Blot and ELISAs were used to quantify protein expression. Cytospins of bronchoalveolar lavage (BAL) cells were used to obtain leukocyte differentials.

Results

MUC18 siRNA reduced IL-13-mediated eotaxin-3 (183 ± 44 vs. 380 ± 59 pg/mL, p < 0.05), while MUC18 overexpression increased IL-13-mediated eotaxin-3 (95 ± 3 vs. 58 ± 3 pg/mL, p < 0.05) in HTBE cells. IL-13-treated Muc18 KO mice had a lower percentage of neutrophils in BAL than WT mice (25 ± 3 vs. 35 ± 3%, p = 0.0565).

Conclusions

These results implicate MUC18 as a potential enhancer of airway inflammation in a type 2 cytokine (e.g., IL-13) milieu.