接触性皮炎是否真与硫柳汞无关

最近，许多研究者声称硫柳汞是筛查接触性皮炎中最无关的一种过敏原。在本诊所对508例疑似接触性过敏性皮炎的患者进行了斑贴试验。同时对他们进行包括医学、人口统计学和职业内容的问卷调查。应用标准化学技术诊断方法（Malmo，Sweden）和其他病例相关的辅助系列检查。对硫柳汞发生过敏反应的相关性评分为1～6。19例（3．7％）对硫柳汞发生过敏反应，其中6例（31．5％）有明确相关性，8例（42．1％）可能相关，仅3例（15．8％）为无关反应。     

Lymphatic Dissemination in Cutaneous Leishmaniasis Following Local Treatment

Cutaneous leishmaniasis (CL) is diverse in its clinical presentation but usually demonstrates an erythematous, infiltrated, ulcerated, and crusted papule or nodule in exposed areas of the body. Rare clinical features have been reported including lymphatic dissemination, usually with subcutaneous nodules along lymphatic channels. Herein, we present six patients suffering from Old World CL with lymphatic dissemination characterized by sporotrichoid subcutaneous nodules along the lymphatic channels draining the primary lesion. Patients'' history, clinical and laboratory findings were collected and summarized. Lymphatic dissemination of CL in our patients manifested as subcutaneous nodules without epidermal involvement within the axis of lymphatic drainage toward the regional lymph node, at times accompanied by regional lymphadenopathy. In all patients, the lymphatic dissemination was not present at initial diagnosis of CL, appearing only after local (topical or intralesional) treatment was initiated. In three patients, the subcutaneous nodules resolved without systemic treatment. Lymphatic dissemination of Old World CL is not uncommon and may possibly be triggered by local treatment. It should be recognized by dermatologists, especially those working in endemic areas. Systemic treatment may be not necessary since spontaneous resolution may occur.Old World cutaneous leishmaniasis (CL) is diverse in its clinical presentation and outcome. The disease spectrum is governed by an interplay between the parasite and the immuno-inflammatory response of the host. The typical clinical presentation of CL is an erythematous, infiltrated, ulcerated, and crusted papule or nodule on any region of the body, with frequent involvement of exposed areas, especially the face and limbs. Lesions heal slowly over a period of months.¹ Although CL often resolves spontaneously, it can result in severe disfiguration. Treatment is usually initiated to hasten healing and prevent scarring.²Old World CL is endemic in Israel and was attributed in the past almost exclusively to Leishmania (Leishmania) major, confined to rural areas of the Negev Desert in southern Israel. Over the last decade, CL due to Leishmania tropica has been increasingly reported in the Judean Desert in central Israel, as well as in northern Israel. Leishmania tropica is often more resistant to treatment and heals more slowly than L. major infections.³Lymphatic dissemination of CL is uncommon but has been reported, usually with dermal or subcutaneous nodules along lymphatic vessels draining the region of the primary lesion.^4–7 Herein, we present six cases of CL with subcutaneous sporotrichoid dissemination after local treatment of the primary lesion, probably caused by lymphatic spread of the parasites. The sporotrichoid dissemination was characterized by deep subcutaneous nodules without any sign of epidermal involvement.The demographic, clinical, and laboratory data of the patients are summarized in 8 performed on tissue obtained from primary lesions (patients 4 and 5) or from subcutaneous nodules (patient 6) confirmed L. tropica infection. Regional lymphadenopathy was noted in two patients (patients 2 and 3). In patients 3 and 6, a biopsy from the subcutaneous nodules established the presence of a deep granulomatous process with Leishmania bodies. After the occurrence of subcutaneous nodules, three patients were treated with intravenous sodium stibogluconate (patient 1, 3, and 4), or with sodium stibogluconate injected directly into the primary cutaneous lesion alone (patient 6) or into both the cutaneous lesion and the subcutaneous nodule (patient 5). The patients experienced total resolution of the primary lesions, the subcutaneous nodules, as well as regional lymphadenopathy. On the parents'' request, intralesional injections of pentostam were terminated after a single treatment in patient 2. The primary lesion eventually healed with a scar and the subcutaneous nodules spontaneously regressed within a few weeks.

Table 1

Demographic, clinical, and laboratory findings

From the Cover: Field-evolved resistance by western corn rootworm to multiple Bacillus thuringiensis toxins in transgenic maize

The widespread planting of crops genetically engineered to produce insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) places intense selective pressure on pest populations to evolve resistance. Western corn rootworm is a key pest of maize, and in continuous maize fields it is often managed through planting of Bt maize. During 2009 and 2010, fields were identified in Iowa in which western corn rootworm imposed severe injury to maize producing Bt toxin Cry3Bb1. Subsequent bioassays revealed Cry3Bb1 resistance in these populations. Here, we report that, during 2011, injury to Bt maize in the field expanded to include mCry3A maize in addition to Cry3Bb1 maize and that laboratory analysis of western corn rootworm from these fields found resistance to Cry3Bb1 and mCry3A and cross-resistance between these toxins. Resistance to Bt maize has persisted in Iowa, with both the number of Bt fields identified with severe root injury and the ability western corn rootworm populations to survive on Cry3Bb1 maize increasing between 2009 and 2011. Additionally, Bt maize targeting western corn rootworm does not produce a high dose of Bt toxin, and the magnitude of resistance associated with feeding injury was less than that seen in a high-dose Bt crop. These first cases of resistance by western corn rootworm highlight the vulnerability of Bt maize to further evolution of resistance from this pest and, more broadly, point to the potential of insects to develop resistance rapidly when Bt crops do not achieve a high dose of Bt toxin.The global area devoted to transgenic crops producing insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) has increased rapidly over the past 15 y, with Bt crops covering more than 69 million hectares in 2012 (1). Most of this area was planted in Bt cotton and Bt maize (1). Benefits of Bt crops include effective management of target pests, decreased use of conventional insecticides, and reduced harm to nontarget organisms (2–5). However, the evolution of resistance could diminish these benefits. The western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), is a major pest of maize, with larval feeding on maize roots and associated management costs causing economic losses in excess of $1 billion per year (6). Through 2013, three Bt toxins have been used in transgenic maize for management of western corn rootworm: Cry3Bb1, mCry3A, and Cry34/35Ab1 (7).In the United States and elsewhere, commercial registration of a Bt crop is accompanied by a resistance-management plan to delay the onset of pest resistance. Resistance management for Bt crops has focused on the refuge strategy, in which refuges of non-Bt crops allow the survival of Bt-susceptible insects, which may mate with resistant insects that survive on the Bt crop (8). To the extent that the heterozygous progeny from these matings have lower fitness on a Bt crop than their Bt-resistant parent, delays in resistance may be achieved, and these delays in resistance increase with the quantity of refuge (9). Additionally, refuges are far more effective in delaying resistance when Bt crops achieve a high dose of toxin against a target pest. High-dose Bt crops kill more than 99.99% of susceptible insects and render resistance a functionally recessive trait (9, 10). None of the currently commercialized Bt maize targeting the western corn rootworm is high dose, so the risk of resistance is increased (11, 12).In 2003, Cry3Bb1 maize was registered by the United States Environmental Protection Agency (US EPA) for management of western corn rootworm larvae (7). In 2009, farmers in Iowa observed severe injury to Cry3Bb1 maize by larval western corn rootworm in the field, and subsequent laboratory assays revealed that this injury was associated with Cry3Bb1 resistance (13). More fields with Cry3Bb1 resistance were identified in 2010 (14), and research in fields identified in 2009 as harboring Cry3Bb1-resistant western corn rootworm found no difference in survival for this pest between non-Bt maize and Cry3Bb1 maize (11). Current threats to Bt maize include the spread of Bt-resistant western corn rootworm and the loss of additional Bt toxins through the presence of cross-resistance. In this paper we report that injury to Cry3Bb1 maize in the field has persisted through 2011 and expanded to include mCry3A maize. Analysis of western corn rootworm collected in 2011 revealed that (i) severe injury to Cry3Bb1 maize and mCry3A maize in the field was associated with resistance, and (ii) cross-resistance between Cry3Bb1 and mCry3A was present. These results demonstrate that insects can evolve resistance rapidly to Bt crops that are not high dose and raise concerns about the adequacy of current resistance-management strategies.     

Mechanotransduction of fluid stresses governs 3D cell migration

Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 µm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK^PY397, F actin, and paxillin-dependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.Integrins and associated focal adhesion (FA) proteins form a tension-sensitive mechanical link between the extracellular matrix (ECM) and the cytoskeleton, and serve as key components in the signaling cascade by which cells transduce mechanical signals into biological responses (mechanotransduction) (1, 2). Contractile stresses generated by the cell are balanced by tractions at cell–substrate adhesions, and the FA protein vinculin accumulates at regions of high substrate stress (3, 4). The FA protein paxillin colocalizes with vinculin (4) and mediates β1-integrin FA turnover through interaction with FA kinase (FAK) (5). The FAK–paxillin signaling axis recruits vinculin to β1 integrins at regions of high matrix adhesion tension (6), and paxillin—a key mechanosensor (7)—mediates protrusion formation at regions of high stress on 2D substrates (8), and FAK–paxillin–vinculin signaling is required for mechanosensing and durotaxis (9).The tumor microenvironment imparts mechanical and chemical signals on tumor and stromal cells (10), and advanced breast carcinomas are characterized by high interstitial fluid pressure (11), an indicator of poor prognosis (12). This elevated fluid pressure drives interstitial flow (IF) and alters chemical transport within the tumor (13), and IF influences tumor cell migration through the generation of autocrine chemokine gradients (14). Equally important, although not as well understood, is the physical drag imparted on the ECM and constitutive cells (15) by IF, which is analogous to the FA-activating shear stresses generated on endothelial cells by hemodynamic forces (16). With endothelial cells, shear stress can be the dominant mechanical stimulus that induces FAK activation and cytoskeletal remodeling; however, for cells embedded within a porous matrix scaffold, the ratio of the force due to the pressure drop across the cell to the total shear force is inversely proportional to hydrogel permeability (SI Appendix, Eq. S5). In this study, we recapitulate physiologically relevant IF through collagen gel within a microfluidic device. Because the permeability of the collagen I hydrogel used in this study is small (1 × 10⁻¹³ m²), the integrated pressure force is more than 30× the integrated shear force for a 20-μm-diameter cell (17) (SI Appendix, Eq. S5). To maintain static equilibrium, all fluid stresses imparted on the cell must be balanced by tension in matrix adhesions. In 2D, the adhesions balancing the fluid drag on the cell are confined to the basal cell surface, whereas in porous media, such as breast stromal ECM, matrix adhesions are distributed across the full cell surface. Consequently, maintaining static equilibrium requires greater adhesion tension on the upstream side of the cell to balance fluid stresses. From the reference frame of the cell, the effect of IF is mechanically equivalent to applying a net outward force at matrix adhesions on the upstream side of the cell, similar to the net tensile stresses applied by use of optical tweezers to study the molecular mechanisms underlying mechanotransduction (4, 18).Here, we demonstrate that the forces required to balance drag imparted on the cell by IF induce a transcellular gradient in matrix adhesion tension, and the tensile stresses at the upstream side of the cell induce FA reorganization and polarization of FA-plaque proteins including vinculin, paxillin, FAK, FAK^PY397, and α-actinin. FA polarization leads to paxillin-dependent actin localization, the formation of protrusions upstream, and rheotaxis. Consistent with the governing mechanism of durotaxis on 2D substrates, this 3D mechanotransduction occurs through FAK and requires paxillin. Importantly, silencing paxillin does not affect cell migration speed but does attenuate rheotaxis. IF is present in many tissues in vivo (19), and because FA polarization and rheotaxis result from a mechanical force balance, this 3D mechanotransduction mechanism may be fundamental to all cells embedded within porous ECM.     

Control of embryonic lung branching morphogenesis by the Rho activator,cytotoxic necrotizing factor 1

BACKGROUND: Lung development is sensitive to physiological stresses, and its development may be impaired by physical distortion, as in patients with congenital diaphragmatic hernia. Yet, little is known about how mechanical forces can influence lung morphogenesis. Studies with cultured cells suggest that cytoskeletal tension may play a key role in growth control. Since the small GTPase Rho plays an important role in the control of cell tension generation, we carried out studies to test the hypothesis that changes in Rho-mediated cell tension may influence branching morphogenesis. METHODS: Embryonic lung buds from timed pregnant Swiss Webster mice were microdissected on Embryonic Day 12 (E12), and whole organs were cultured in serum-free medium in the presence of the Rho activator cytotoxic necrotizing factor 1 (CNF-1) for 48 h. Serial measurements of the degree of epithelial branch formation and tissue maturation were performed using light microscopy and computerized image analysis. RESULTS: At 48 h, embryonic lungs treated with 2 ng/ml CNF-1 increased their terminal bud count by 236 +/- 18% (P = 0.01) compared with 132 +/- 2% for untreated controls. However, dose-response experiments revealed biphasic behavior: at a higher dose of CNF-1 (200 ng/ml), bud number was actually decreased relative to controls (43 +/- 1%, P < 0.001). Histological analysis revealed that individual glands appeared to be more highly developed at low-dose CNF-1, whereas the high dose produced gland contraction. CONCLUSIONS: These data support a potential role for Rho and cytoskeletal tension in control of epithelial pattern formation during lung development.     

Cell tension, matrix mechanics, and cancer development

Oncologists often diagnose cancer based on a change of tissue stiffness sensed by palpation, yet cancer researchers generally focus on biochemical signaling mechanisms. Tumors are more rigid because they have a stiffer extracellular matrix. A new study shows that this alteration of matrix mechanics activates integrins, which not only promotes mitogenic signaling through Erk but also cell contractility through Rho, which can further increase matrix stiffness. This establishes a positive feedback loop that switches on the malignant phenotype in mammary epithelial cells. This mechanical "autocrine loop" brings solid-state mechanotransduction on a par with oncogenic signaling pathways in malignant transformation.     

Thimerosal – Is it really irrelevant?

Recently, several investigators claimed that thimerosal is one of the most irrelevant allergens existing in screening for contact dermatitis. 508 patients who were suspected to have allergic contact dermatitis were patch tested at our clinic. They completed a questionnaire including medical, demographic and occupational details. We used the standard tray of chemotechnique diagnostics (Malmö, Sweden) and additional series, which were case relevant. The relevance of the allergic reaction to thimerosal was scored from 1 to 6. 19 patients (3.7%) had an allergic reaction to thimerosal. 6 (31.5%) had a definite relevance and 8 (42.1%) had a probable relevance. Only 3 patients (15.8%) had an irrelevant reaction. SPIN value (significance–prevalence index number) was 2281. We found a high proportion of mechanics (42.1%) among the patients who had positive reaction to thimerosal (P < 0.0001). Although previous reports found thimerosal highly irrelevant, our daily experience being supported by the above data indicates that positive reactions to thimerosal could be relevant for many patients.     

Angiostatic steroids. Method of discovery and mechanism of action

A new class of steroids has been found that inhibits angiogenesis in the presence of nonanticoagulant heparin. Tetrahydrocortisol is the most potent of the naturally occurring angiostatic steroids. It is a metabolite of cortisone that circulates in the blood, appears in the urine, and was previously believed to be biologically inactive. Both the plasma form and the urinary form are antiangiogenic. The mechanism of action of these steroids depends on their ability to specifically alter basement membrane turnover in growing capillary blood vessels. These steroids represent a prototype of angiogenesis inhibitors that may find potential therapeutic use as adjuncts to anticancer therapy, and in diseases dominated by abnormal neovascularization, i.e., angiogenesis-dependent diseases.