Effects of systematic patient education in skin care and protection in a hand eczema clinic.

BACKGROUND: Hand eczema has a high impact on patients' quality of life. The treatment focuses on improving skin barrier function. OBJECTIVES: To evaluate the effects and acceptance of a novel educational program for patients with hand eczema. METHODS: Retrospectively, the records of 36 patients who attended the prevention program and follow-up visits were analyzed. Physician global assessment (PGA) scores, acceptance and behavioral changes were assessed. RESULTS: In 67% of patients, an improvement of the hand eczema could be attributed to the effects of our educational program. The mean PGA score significantly decreased from 3 before education to 2.2 during follow-up. Behavioral changes in both skin care and protection were reported in 81 and 86%, respectively. CONCLUSIONS: Our educational program had a positive effect on clinical outcome as well as adherence to skin care and protection measures. Its integration in a hand eczema clinic was feasible and well accepted by the patients.

Methylaminolevulinic acid-based photodynamic therapy: the patient's view.

Topical photodynamic therapy (PDT) with methylaminolevulinate (MAL) for nonmelanomatous skin cancers (NMSC) has proven efficient and safe. Because pain and a phototoxic reaction (PTR) are frequent side effects, the ability to predict discomfort may improve the management of patient care. During a 3-month period, we enrolled 46 patients with a total of 120 precancerous actinic skin lesions or NMSCs. Patients were treated with MAL-PDT, and follow-up continued for 8 wk. PDT had no lasting side effects in 65% of the lesions, and nearly 90% healed. The most frequent adverse cosmetic effect was skin discoloration (26.7%). Scarring was observed more often on the nose (21%, 3 of 14 lesions). Women experienced erythema more often than men (24% vs. 6%). With approximately 80% of the lesions, the patient reported light or no PTR. The average patient-reported pain during irradiation was moderate (4.92 on a scale of 0 to 10). Pain was persistent in 45% of the cases, but it decreased rapidly thereafter (on average 1 d). Risk factors for a greater severity of pain were lesions on the scalp (average pain score: 6.62) and on the forehead (average: 7.00) and treatment over an extended area (average: 7.32). Treatment on the nose (average: 3.29) or on the thorax (average: 3.00) was less painful. The final level of satisfaction reported was good or very good by 90% of the patients. Based on our results, eligible patients can be individually identified and informed in advance about the likelihood of side effects, thereby improving their satisfaction.

The redox sensor TXNL1 plays a regulatory role in fluid phase endocytosis.

BACKGROUND: Small GTPases of the Rab family can cycle between a GTP- and a GDP-bound state and also between membrane and cytosol. The latter cycle is mediated by the Guanine Nucleotide Dissociation Inhibitor GDI, which can selectively extract GDP-bound Rab proteins from donor membranes, and then reload them on target membranes. In previous studies, we found that capture of the small GTPase Rab5, a key regulator of endocytic membrane traffic, by GDI is stimulated by oxidative stress via p38MAPK, resulting in increased fluid phase endocytosis. METHODOLOGY/PRINCIPAL FINDINGS: When purifying the GDI stimulating activity we found that that it copurified with a high MW protein complex, which included p38MAPK. Here we report the identification and characterization of another component of this complex as the thioredoxin-like protein TXNL1. Our observations indicate that TXNL1 play a selective role in the regulation of fluid phase endocytosis, by controlling GDI capacity to capture Rab5. CONCLUSIONS/SIGNIFICANCE: Oxidants, which are known to cause cellular damage, can also trigger signaling pathways, in particular via members of the thioredoxin family. We propose that TXNL1 acts as an effector of oxidants or a redox sensor by converting redox changes into changes of GDI capacity to capture Rab5, which in turn modulates fluid phase endocytosis.

Intracellular trafficking of interleukin-1 receptor I requires Tollip.

Interleukin-1 receptor (IL-1RI) is a master regulator of inflammation and innate immunity. When triggered by IL-1beta, IL-1RI aggregates with IL-1R-associated protein (IL-1RAcP) and forms a membrane proximal signalosome that potently activates downstream signaling cascades. IL-1beta also rapidly triggers endocytosis of IL-1RI. Although internalization of IL-1RI significantly impacts signaling, very little is known about trafficking of IL-1RI and therefore about precisely how endocytosis modulates the overall cellular response to IL-1beta. Upon internalization, activated receptors are often sorted through endosomes and delivered to lysosomes for degradation. This is a highly regulated process that requires ubiquitination of cargo proteins as well as protein-sorting complexes that specifically recognize ubiquitinated cargo. Here, we show that IL-1beta induces ubiquitination of IL-1RI and that via these attached ubiquitin groups, IL-1RI interacts with the ubiquitin-binding protein Tollip. By using an assay to follow trafficking of IL-1RI from the cell surface to late endosomes and lysosomes, we demonstrate that Tollip is required for sorting of IL-1RI at late endosomes. In Tollip-deficient cells and cells expressing only mutated Tollip (incapable of binding IL-1RI and ubiquitin), IL-1RI accumulates on late endosomes and is not efficiently degraded. Furthermore, we show that IL-1RI interacts with Tom1, an ubiquitin-, clathrin-, and Tollip-binding protein, and that Tom1 knockdown also results in the accumulation of IL-1RI at late endosomes. Our findings suggest that Tollip functions as an endosomal adaptor linking IL-1RI, via Tom1, to the endosomal degradation machinery.

Capture of the small GTPase Rab5 by GDI: regulation by p38 MAP kinase.

The small GTPase Rab5 is one of the key regulators of early endocytic traffic and, like other GTPases, cycles between GTP- and GDP-bound states as well as between membrane and cytosol. The latter cycle is controlled by a guanine nucleotide dissociation inhibitor (GDI), which functions as a Rab vehicle in the cytosol. GDI extracts from membranes the inactive GDP-bound form of the Rab. Then, the cytosolic GDI:Rab complex is delivered to the appropriate target membrane, where the Rab protein is reloaded, presumably via a GDI displacement factor (Pfeffer and Aivazian, 2004). We previously reported that the formation of the GDI:Rab5 complex is stimulated by the mitogen-activated protein kinase p38 (Cavalli et al., 2001). Mol. Cell7, 421-432.]. Selective activation of p38 MAPK increases endocytic rates in vivo, presumably allowing more efficient internalization of cell surface components for repair, storage, or degradation. These observations emphasize the possibility that external stimuli contribute to the regulation of membrane traffic. Here, we describe how to monitor the ability of GDI to extract Rab5 from early endosomal membranes in vitro and the role of p38 MAPK in this process. In addition, we detail how to investigate the possible role of p38 MAPK in the regulation of endocytosis in vivo.

Signaling from the far side.

Signaling by cell surface receptors is often turned off by receptor endocytosis and downregulation. However, it appears that some signaling pathways continue to fire from within cells. A recent study now suggests that a late endosomal p14/MP1-MAPK scaffold complex is critical for the ERK signaling pathway.

Late endosome motility depends on lipids via the small GTPase Rab7.

We report that lipids contribute to regulate the bidirectional motility of late endocytic compartments. Late endocytic vesicles loaded with cholesterol lose their dynamic properties, and become essentially immobile, including in cells from Niemann-Pick C patients. These vesicles then retain cytoplasmic dynein activity, but seem to be unable to acquire kinesin activity, eventually leading to paralysis. Our data suggest that this defect depends on the small GTPase Rab7, since the motility of vesicles loaded with cholesterol can be restored by the Rab7 inhibitory mutant N125I. Conversely, wild-type Rab7 overexpression mimics the effects of cholesterol on motility in control cells. Consistently, cholesterol accumulation increases the amounts of membrane-associated Rab7, and inhibits Rab7 membrane extraction by the guanine nucleotide dissociation inhibitor. Our observations thus indicate that cholesterol contributes to regulate the Rab7 cycle, and that Rab7 in turn controls the net movement of late endocytic elements. We conclude that motor functions can be regulated by the membrane lipid composition via the Rab7 cycle.