Background
Hereditary angioedema is a potentially life‐threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of ...avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short‐term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures.
Methods
We conducted a retrospective analysis before and a prospective survey after establishing the diagnosis in a group of 137 (60 males, 77 females; 20 pediatric and 117 adult) patients with HAE. Both were implemented using questionnaires, patient diaries and hospital charts focusing on medical interventions provoking edematous attack, and the medicinal products (C1‐INH concentrate, tranexamic acid, and danazol) administered for STP.
Results
Comparing surgical interventions performed without pre‐event STP (in 39/89 patients before HAE was diagnosed), or after STP (in 3/55 cases after diagnosis), we found a significant (P < 0.0001, Fisher's exact test) reduction in the number of edematous episodes. Evaluating the efficacy of the drugs administered for STP revealed that C1‐INH concentrate (Berinert®, CSL Behring, Marburg, Germany) was significantly (P = 0.0096, Fisher's exact test) superior to orally administered drugs in reducing the instances of postprocedural edema. None of the medicinal products caused adverse events potentially related to STP.
Conclusions
STP reduces the number of postprocedural edematous episodes. C1‐INH concentrate is safe and effective for prophylaxis. When this agent is not available, danazol is a potential alternative for prophylaxis before elective medical interventions.
To identify the cortical sites where 5-hydroxytryptamine 2A (5-HT 2A ) serotonin receptors respond to the action of hallucinogens and atypical antipsychotic drugs, we have examined the cellular and ...subcellular distribution of these receptors in the cerebral cortex of macaque monkeys (with a focus on prefrontal areas) by using light and electron microscopic immunocytochemical techniques. 5-HT 2A receptor immunoreactivity was detected in all cortical layers, among which layers II and III and layers V and VI were intensely stained, and layer IV was weakly labeled. The majority of the receptor-labeled cells were pyramidal neurons and the most intense immunolabeling was consistently confined to their parallelly aligned proximal apical dendrites that formed two intensely stained bands above and below layer IV. In double-label experiments, 5-HT 2A label was found in calbindin D28k-positive, nonphosphorylated-neurofilament-positive, and immuno-negative pyramidal cells, suggesting that probably all pyramidal cells express 5-HT 2A receptors. 5-HT 2A label was also found in large- and medium-size interneurons, some of which were immuno-positive for calbindin. 5-HT 2A receptor label was also associated with axon terminals. These findings reconcile the data on the receptor’s cortical physiology and localization by ( i ) establishing that 5-HT 2A receptors are located postsynaptically and presynaptically, ( ii ) demonstrating that pyramidal neurons constitute the major 5-HT 2A -receptor-expressing cells in the cortex, and ( iii ) supporting the view that the apical dendritic field proximal to the pyramidal cell soma is the “hot spot” for 5-HT 2A -receptor-mediated physiological actions relevant to normal and “psychotic” functional states of the cerebral cortex. dorsolateral prefrontal cortex macaque monkey inhibitory interneuron schizophrenia clozapine
The presence of anti-C1-inhibitor (anti-C1-INH) autoantibodies is a hallmark of acquired C1-inhibitor deficiency. However, only scarce data are available on their prevalence, diagnostic value, and/or ...significance in systemic lupus erythematosus (SLE). In a multicentre study, we determined the levels of autoantibodies to C1-inhibitor in sera from 202 patients with SLE and 134 healthy controls. Additional clinical and laboratory parameters, such as organ involvement, as well as anti-C1q, anti-double-stranded DNA antibody, erythrocyte sedimentation rate, C-reactive protein, C3 and C4 serum complement levels have been studied in patients. The level of anti-C1-INH IgG was significantly higher (p = 0.034) in SLE patients, than in the controls. A high anti-C1-INH level of ≥0.4 U/ml (mean of controls + 2 SD) was found in 17% of the patients, but in only 4% of the controls (p = 0.0003). The SLEDAI score was significantly higher (p = 0.048) and the duration of SLE was significantly longer (p = 0.0004) among patients with elevated anti-C1-INH levels compared with patients without this autoantibody (median disease duration 8 vs. 17 years, respectively). Anti-C1-INH level was not correlated with any other laboratory parameter or organ manifestation of the disease. These findings indicate that the anti-C1-INH level is higher in SLE patients than in healthy controls and furthermore, the anti-C1-INH level correlates with the duration and activity of the disease. Lupus (2010) 19, 634—638.
Characterization of CFTR High Expresser cells in the intestine Jakab, Robert L; Collaco, Anne M; Ameen, Nadia A
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
09/2013, Letnik:
305, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The CFTR High Expresser (CHE) cells express eightfold higher levels of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel compared with neighboring enterocytes and were ...first identified by our laboratory (Ameen et al., Gastroenterology 108: 1016, 1995). We used double-label immunofluorescence microscopy to further study these enigmatic epithelial cells in rat intestine in vivo or ex vivo. CHE cells were found in duodenum, most frequent in proximal jejunum, and absent in ileum and colon. CFTR abundance increased in CHE cells along the crypt-villus axis. The basolateral Na(+)K(+)Cl(-) cotransporter NKCC1, a key transporter involved in Cl(-) secretion, was detected at similar levels in CHE cells and neighboring enterocytes at steady state. Microvilli appeared shorter in CHE cells, with low levels of Myosin 1a, a villus enterocyte-specific motor that retains sucrase/isomaltase in the brush-border membrane (BBM). CHE cells lacked alkaline phosphatase and absorptive villus enterocyte BBM proteins, including Na(+)H(+) exchanger NHE3, Cl(-)/HCO3(-) exchanger SLC26A6 (putative anion exchanger 1), and sucrase/isomaltase. High levels of the vacuolar-ATPase proton pump were observed in the apical domain of CHE cells. Levels of the NHE regulatory factor NHERF1, Na-K-ATPase, and Syntaxin 3 were similar to that of neighboring enterocytes. cAMP or acetylcholine stimulation robustly increased apical CFTR and basolateral NKCC1 disproportionately in CHE cells relative to neighboring enterocytes. These data strongly argue for a specialized role of CHE cells in Cl(-)-mediated "high-volume" fluid secretion on the villi of the proximal small intestine.
Background and Aim
Lubiprostone is a chloride channel activator in clinical use for the treatment of chronic constipation, but the mechanisms of action of the drug are poorly understood. The aim of ...this study was to determine whether lubiprostone exerts secretory effects in the intestine by membrane trafficking of ion transporters and associated machinery.
Methods
Immunolabeling and quantitative fluorescence intensity were used to examine lubiprostone-induced trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR), sodium/potassium-coupled chloride co-transporter 1 (NKCC1), electrogenic sodium/bicarbonate co-transporter 1 (NBCe1), down-regulated in adenoma (DRA), putative anion transporter 1 (PAT1), sodium/proton exchanger 3 (NHE3), Ca
2+
activated chloride channel 2 (ClC-2) serotonin and its transporter SERT, E prostanoid receptors EP4 and EP1, sodium/potassium ATPase (Na–K-ATPase) and protein kinase A (PKA). The effects of lubiprostone on mucus exocytosis in rat intestine and human rectosigmoid explants were also examined.
Results
Lubiprostone induced contraction of villi and proximal colonic
plicae
and membrane trafficking of transporters that was more pronounced in villus/surface cells compared to the crypt. Membrane trafficking was determined by: (1) increased membrane labeling for CFTR, PAT1, NKCC1, and NBCe1 and decreased membrane labeling for NHE3, DRA and ClC-2; (2) increased serotonin, SERT, EP4, EP1 and PKA labeling in enterochromaffin cells; (3) increased SERT, EP4, EP1, PKA and Na–K-ATPase in enterocytes; and (4) increased mucus exocytosis in goblet cells.
Conclusion
These data suggest that lubiprostone can target serotonergic, EP4/PKA and EP1 signaling in surface/villus regions; stimulate membrane trafficking of CFTR/NBCe1/NKCC1 in villus epithelia and PAT1/NBCe1/NKCC1 in colonic surface epithelia; suppress NHE3/DRA trafficking and fluid absorption; and enhance mucus-mobilization and mucosal contractility.
SUMMARY
Effects of 2 dietary levels (0.6 and 1.0 ppm) of T-2 toxin, and the possible protective capacity of a mycotoxin-inactivating feed additive (Detoxa Plus) were investigated in growing White ...Pekin ducklings in a 49-d trial comprising 6 treatment groups of 10 ducks/group. The experimental design consisted of 1 negative and 1 positive control and 4 test groups, as follows: group 1, negative control (no T-2 toxin and no feed additive added to the feeds); group 2, positive control (no T-2 toxin added, but the feeds were supplemented with feed additive at 2 kg/t); group 3, feeds were complemented with 0.6 ppm of purified T-2 toxin (no feed additive added); group 4, feeds were complemented with 0.6 ppm of T-2 toxin and 2 kg/t of the feed additive was provided; group 5, feeds were complemented with 1.0 ppm of T-2 toxin (no feed additive added); group 6, feeds were complemented with 1.0 ppm of T-2 toxin and 2 kg/t of the feed additive was provided. From wk 4 until the end of the trial, the daily BW gain of group 3 ducks was inferior to that of control ducks, and the differences in means were statistically significant (P ≤ 0.05) at wk 4 and 7. The final BW of this group was also significantly lower than that of the control (P ≤ 0.001). The BW gain of ducks in group 5 was also depressed by the toxin treatment. The adverse effect of 0.6 ppm of T-2 toxin was fully counteracted by the feed additive in terms of daily BW gain, cumulative daily BW gain, and BW at exsanguination. The T-2 toxin at both treatment levels depressed the blastogenic response of lymphocytes to nonspecific mitogens (concanavalin A and phytohaemagglutinin), which was counteracted by the feed additive at the lower dietary concentration of T-2 toxin. No such effect was observed with 1.0 ppm of T-2 toxin. Metabolic blood parameters and hematological data showed no consistent treatment effects. We conclude that this feed additive is able to counteract the adverse effects of T-2 toxin at dietary concentrations that might be encountered under field conditions.
Changes in intestinal luminal pH affect mucosal ion transport. The aim of this study was to compare how luminal pH and specific second messengers modulate the membrane traffic of four major ion ...transporters (CFTR, NHE3, NKCC1, and NBCe1) in rat small intestine. Ligated duodenal, jejunal, and ileal segments were infused with acidic or alkaline saline, 8-Br-cAMP, or the calcium agonist carbachol in vivo for 20 min. Compared with untreated intestine, lumen pH was reduced after cAMP or carbachol and increased following HCO(3)(-)-saline. Following HCl-saline, lumen pH was restored to control pH levels. All four secretory stimuli resulted in brush-border membrane (BBM) recruitment of CFTR in crypts and villi. In villus enterocytes, CFTR recruitment was coincident with internalization of BBM NHE3 and basolateral membrane recruitment of the bicarbonate transporter NBCe1. Both cAMP and carbachol recruited NKCC1 to the basolateral membrane of enterocytes, while luminal acid or HCO(3)(-) retained NKCC1 in intracellular vesicles. Luminal acid resulted in robust recruitment of CFTR and NBCe1 to their respective enterocyte membrane domains in the upper third of the villi; luminal HCO(3)(-) induced similar membrane changes lower in the villi. These findings indicate that each stimulus promotes a specific transporter trafficking response along the crypt-villus axis. This is the first demonstration that physiologically relevant secretory stimuli exert their actions in villus enterocytes by membrane recruitment of CFTR and NBCe1 in tandem with NHE3 internalization.
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