Rapid estimation of 2D relative B 1 + -maps from localizers in the human heart at 7T using deep learning.

PURPOSE: Subject-tailored parallel transmission pulses for ultra-high fields body applications are typically calculated based on subject-specific B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps of all transmit channels, which require lengthy adjustment times. This study investigates the feasibility of using deep learning to estimate complex, channel-wise, relative 2D B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps from a single gradient echo localizer to overcome long calibration times. METHODS: 126 channel-wise, complex, relative 2D B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps of the human heart from 44 subjects were acquired at 7T using a Cartesian, cardiac gradient-echo sequence obtained under breath-hold to create a library for network training and cross-validation. The deep learning predicted maps were qualitatively compared to the ground truth. Phase-only B 1 + $$ {\mathrm{B}}_1^{+} $$ -shimming was subsequently performed on the estimated B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps for a region of interest covering the heart. The proposed network was applied at 7T to 3 unseen test subjects. RESULTS: The deep learning-based B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps, derived in approximately 0.2 seconds, match the ground truth for the magnitude and phase. The static, phase-only pulse design performs best when maximizing the mean transmission efficiency. In-vivo application of the proposed network to unseen subjects demonstrates the feasibility of this approach: the network yields predicted B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps comparable to the acquired ground truth and anatomical scans reflect the resulting B 1 + $$ {\mathrm{B}}_1^{+} $$ -pattern using the deep learning-based maps. CONCLUSION: The feasibility of estimating 2D relative B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps from initial localizer scans of the human heart at 7T using deep learning is successfully demonstrated. Because the technique requires only sub-seconds to derive channel-wise B 1 + $$ {\mathrm{B}}_1^{+} $$ -maps, it offers high potential for advancing clinical body imaging at ultra-high fields.

Respiration induced B1+ changes and their impact on universal and tailored 3D kT-point parallel transmission pulses for 7T cardiac imaging.

PURPOSE: Human heart imaging at ultra-high fields is highly challenging because of respiratory motion-induced artefacts and spatially heterogeneous B1+ profiles. This work demonstrates that respiration resolved 3D B1+ -maps can be used with a dedicated tailored and universal parallel transmission (pTx) pulse design to compensate respiration related B1+ changes in subjects performing shallow and deep breathing (SB/DB). METHODS: Three-dimensional (3D) B1+ -maps of the thorax were acquired in 31 subjects under SB and in 15 subjects under SB and DB. Different universal and tailored non-selective pTx pulses were designed from non-respiration resolved (NRR) and respiration resolved (RR) reconstructions of the SB/DB B1+ -maps. The performance of all pulses was tested with RR-SB/DB B1+ -maps. Respiration-robust tailored and universal pulses were applied in vivo in 5 subjects at 7T in 3D gradient-echo free-breathing scans. RESULTS: All optimized pTx pulses performed well for SB. For DB, however, only the universal and the tailored respiration-robust pulses achieved homogeneous flip angles (FAs) in all subjects and across all respiration states, whereas the tailored respiration-specific pulses resulted in a higher FA variation. The respiration-robust universal pulse resulted in an average coefficient of variation in the FA maps of 12.6% compared to 8.2% achieved by tailored respiration-robust pulses. In vivo measurements at 7T demonstrate the benefits of using respiration-robust pulses for DB. CONCLUSION: Universal and tailored respiration-robust pTx pulses based on RR B1+ -maps are highly preferred to achieve 3D heart FA homogenization at 7T when subjects perform DB, whereas universal and tailored pulses based on NRR B1+ -maps are sufficient when subjects perform SB.

Calibration-free pTx of the human heart at 7T via 3D universal pulses.

PURPOSE: MRI at ultra-high fields in the human body is highly challenging and requires lengthy calibration times to compensate for spatially heterogeneous B1+ profiles. This study investigates the feasibility of using pre-computed universal pulses for calibration-free homogeneous 3D flip angle distribution in the human heart at 7T. METHODS: Twenty-two channel-wise 3D B1+ data sets were acquired under free-breathing in 19 subjects to generate a library for an offline universal pulse (UP) design (group 1: 12 males [M] and 7 females [F], 21-66 years, 19.8-28.3 kg/m2 ). Three of these subjects (2M/1F, 21-33 years, 20.8-23.6 kg/m2 ) were re-scanned on different days. A 4kT-points UP optimized for the 22 channel-wise 3D B1+ data sets in group 1 (UP22-4kT) is proposed and applied at 7T in 9 new and unseen subjects (group 2: 4M/5F, 25-56 years, 19.5-35.3 kg/m2 ). Multiple tailored and universal static and dynamic parallel-transmit (pTx) pulses were designed and evaluated for different permutations of the B1+ data sets in group 1 and 2. RESULTS: The proposed UP22-4kT provides low B1+ variation in all subjects, seen and unseen, without severe signal drops. Experimental data at 7T acquired with UP22-4kT shows comparable image quality as data acquired with tailored-4kT pulses and demonstrates successful calibration-free pTx of the human heart. CONCLUSION: UP22-4kT allows for calibration-free homogeneous flip angle distributions across the human heart at 7T. Large inter-subject variations because of sex, age, and body mass index are well tolerated. The proposed universal pulse removes the need for lengthy (10-15 min) calibration scans and therefore has the potential to bring body imaging at 7T closer to the clinical application.

Motion-compensated fat-water imaging for 3D cardiac MRI at ultra-high fields.

PURPOSE: Respiratory motion-compensated (MC) 3D cardiac fat-water imaging at 7T. METHODS: Free-breathing bipolar 3D triple-echo gradient-recalled-echo (GRE) data with radial phase-encoding (RPE) trajectory were acquired in 11 healthy volunteers (7M\4F, 21-35 years, mean: 30 years) with a wide range of body mass index (BMI; 19.9-34.0 kg/m2 ) and volunteer tailored B1+ shimming. The bipolar-corrected triple-echo GRE-RPE data were binned into different respiratory phases (self-navigation) and were used for the estimation of non-rigid motion vector fields (MF) and respiratory resolved (RR) maps of the main magnetic field deviations (ΔB0 ). RR ΔB0 maps and MC ΔB0 maps were compared to a reference respiratory phase to assess respiration-induced changes. Subsequently, cardiac binned fat-water images were obtained using a model-based, respiratory motion-corrected image reconstruction. RESULTS: The 3D cardiac fat-water imaging at 7T was successfully demonstrated. Local respiration-induced frequency shifts in MC ΔB0 maps are small compared to the chemical shifts used in the multi-peak model. Compared to the reference exhale ΔB0 map these changes are in the order of 10 Hz on average. Cardiac binned MC fat-water reconstruction reduced respiration induced blurring in the fat-water images, and flow artifacts are reduced in the end-diastolic fat-water separated images. CONCLUSION: This work demonstrates the feasibility of 3D fat-water imaging at UHF for the entire human heart despite spatial and temporal B1+ and B0 variations, as well as respiratory and cardiac motion.

32-Channel self-grounded bow-tie transceiver array for cardiac MR at 7.0T.

PURPOSE: Design, implementation, evaluation, and application of a 32-channel Self-Grounded Bow-Tie (SGBT) transceiver array for cardiac MR (CMR) at 7.0T. METHODS: The array consists of 32 compact SGBT building blocks. Transmission field ( B1+ ) shimming and radiofrequency safety assessment were performed with numerical simulations and benchmarked against phantom experiments. In vivo B1+ efficiency mapping was conducted with actual flip angle imaging. The array's applicability for accelerated high spatial resolution 2D FLASH CINE imaging of the heart was examined in a volunteer study (n = 7). RESULTS: B1+ shimming provided a uniform field distribution suitable for female and male subjects. Phantom studies demonstrated an excellent agreement between simulated and measured B1+ efficiency maps (7% mean difference). The SGBT array afforded a spatial resolution of (0.8 × 0.8 × 2.5) mm3 for 2D CINE FLASH which is by a factor of 12 superior to standardized cardiovascular MR (CMR) protocols. The density of the SGBT array supports 1D acceleration of up to R = 4 (mean signal-to-noise ratio (whole heart) ≥ 16.7, mean contrast-to-noise ratio ≥ 13.5) without impairing image quality significantly. CONCLUSION: The compact SGBT building block facilitates a modular high-density array that supports accelerated and high spatial resolution CMR at 7.0T. The array provides a technological basis for future clinical assessment of parallel transmission techniques.

3D Free-breathing multichannel absolute B1+ Mapping in the human body at 7T.

PURPOSE: To introduce and investigate a method for free-breathing three-dimensional (3D) B1+ mapping of the human body at ultrahigh field (UHF), which can be used to generate homogenous flip angle (FA) distributions in the human body at UHF. METHODS: A 3D relative B1+ mapping sequence with a radial phase-encoding (RPE) k-space trajectory was developed and applied in 11 healthy subjects at 7T. An RPE-based actual flip angle mapping method was applied with a dedicated B1+ shim setting to calibrate the relative B1+ maps yielding absolute B1+ maps of the individual transmit channels. The method was evaluated in a motion phantom and by multidimensional in vivo measurements. Additionally, 3D gradient echo scans with and without static phase-only B1+ shims were used to qualitatively validate B1+ shim predictions. RESULTS: The phantom validation revealed good agreement for B1+ maps between dynamic measurement and static reference acquisition. The proposed 3D method was successfully validated in vivo by comparing magnitude and phase distributions with a 2D Cartesian reference. 3D B1+ maps free from visible motion artifacts were successfully acquired for 11 subjects with body mass indexes ranging from 19 kg/m2 to 34 kg/m2 . 3D respiration-resolved absolute B1+ maps indicated FA differences between inhalation and exhalation up to 15% for one channel and up to 24% for combined channels for shallow breathing. CONCLUSION: The proposed method provides respiration-resolved absolute 3D B1+ maps of the human body at UHF, which enables the investigation and development of 3D B1+ shimming and parallel transmission methods to further enhance body imaging at UHF.

Three-dimensional static and dynamic parallel transmission of the human heart at 7 T.

Three-dimensional (3D) human heart imaging at ultra-high fields is highly challenging due to respiratory and cardiac motion-induced artifacts as well as spatially heterogeneous B1+ profiles. In this study, we investigate the feasibility of applying 3D flip angle (FA) homogenization targeting the whole heart via static phase-only and dynamic kT-point in vivo parallel transmission at 7 T. 3D B1+ maps of the thorax were acquired under free breathing in eight subjects to compute parallel transmission pulses that improve excitation homogeneity in the human heart. To analyze the number of kT-points required, excitation homogeneity and radiofrequency (RF) power were compared using different regions of interest in six subjects with different body mass index (BMI) values of 20-34 kg/m2 for a wide range of regularization parameters. One subset of the optimized subject-specific pulses was applied in vivo on a 7 T scanner for six subjects in Cartesian 3D breath-hold scans as well as in two subjects in a radial phase-encoded 3D free-breathing scan. Across all subjects, 3-4 kT-points achieved a good tradeoff between RF power and nominal FA homogeneity. For subjects with a BMI in the normal range, the 4 kT-point pulses reliably improved the coefficient of variation by less than 10% compared with less than 25% achieved by static phase-only parallel transmission. in vivo measurements on a 7 T scanner validated the B1+ estimations and the pulse design, despite neglecting ΔB0 in the optimizations and Bloch simulations. This study demonstrates in vivo that kT-point pTx pulses are highly suitable for mitigating nominal FA heterogeneities across the entire 3D heart volume at 7 T. Furthermore, 3-4 kT-points demonstrate a practical tradeoff between nominal FA heterogeneity mitigation and RF power.

Drainage network dynamics in an agricultural headwater sub-basin.

Headwaters provide many ecosystems services. Currently, these vulnerable systems are subject to threats related to human activities. This work aims to analyse the spatial pattern changes (expansion/contraction) in the drainage network (DN) of a headwater sub-basin under agriculture between 1966 and 2019 in the Argentine Pampas Region. We study and discuss the hydrometeorological and land use context to understand the spatial and temporal dynamics of the DN, and propose a conceptual model that synthesizes the complex interactions between the factors involved in that dynamics. A broad (1950-2019, at the Del Azul Creek basin) and a short (1996-2019, at the sub-basin of the Videla Creek -SVC-) temporal and spatial scale analysis of data were carried out. We studied rainfall, evapotranspiration, water table depth, streamflow and land use. Temporal and spatial changes in the DN of the SVC were analysed by aerial photos and historical satellite images. Four wet and three dry periods were identified, and close surface-subsurface water interactions typical of plains, were found. The area under agriculture showed a first gradual increase (1975-2012), which turned sharp from 2012 (30,908 ha year-1), with a leading role of soybeans' sown area. The area of the DN increased 1.4699*105 m2 between 1966 and 2010, both under dry conditions, which evidenced its expansion. The study of the flatlands' particular hydrology within the current land use and management trends provided key elements to understand DN area's changes. Complex interactions between processes associated with climatic forcing and the system's sensitivity (its state to receive and process the inputs), are involved in the spatial and temporal dynamics of the DN. Our work improves the understanding of the functioning of these vulnerable systems within agricultural areas, nowadays under productive pressures associated with increasing global food demand, and threats to changes in the hydrological dynamics by global change.

High Macrophage Densities in Native Kidney Biopsies Correlate With Renal Dysfunction and Promote ESRD.

Introduction: Macrophages and monocytes are main players in innate immunity. The relevance of mononuclear phagocyte infiltrates on clinical outcomes remains to be determined in native kidney diseases. Methods: Our cross-sectional study included 324 patients with diagnostic renal biopsies comprising 17 disease entities and normal renal tissues for comparison. All samples were stained for CD68+ macrophages. Selected groups were further subtyped for CD14+ monocytes and CD163+ alternatively activated macrophages. Using precise pixel-based digital measurements, we quantified cell densities as positively stained areas in renal cortex and medulla as well as whole renal tissue. Laboratory and clinical data of all cases at the time of biopsy and additional follow-up data in 158 cases were accessible. Results: Biopsies with renal disease consistently revealed higher CD68+-macrophage densities and CD163+-macrophage densities in cortex and medulla compared to controls. High macrophage densities correlated with impaired renal function at biopsy and at follow-up in all diseases and in diseases analyzed separately. High cortical CD68+-macrophage densities preceded shorter renal survival, defined as requirement of permanent dialysis. CD14+ monocyte densities showed no difference compared to controls and did not correlate with renal function. Conclusion: Precise quantification of macrophage densities in renal biopsies may contribute to risk stratification to identify patients with high risk for end-stage renal disease (ESRD) and might be a promising therapeutic target in renal disease.

[Perforator based flaps of lateral thoracic artery (LTAP) and thoracodorsal artery (TDAP) for axillary reconstruction in patients with hidradenitis suppurativa]. / Die Verwendung lokaler Perforatorlappenplastiken der Arteria thoracica lateralis (LTAP) und Arteria thoracodorsalis (TDAP) zur axillären Rekonstruktion bei Hidradenitis suppurativa.

Hidradenitis suppurativa is a chronic inflammatory disease of apocrine gland-bearing skin, especially in the axilla. The coverage of large defects in the region of the axilla after radical resection poses a challenge to reconstructive surgery. The lateral chest offers, among others, two options for perforator flaps: the thoracodorsal artery perforator flap and the lateral thoracic artery perforator flap. This article introduces the lateral thoracic artery flap as an additional option for defect restoration alongside the thoracodorsal artery perforator flap. A total of 13 flaps (10 lateral thoracic artery perforator flaps and 3 thoracodorsal artery perforator flaps) were used for defect reconstruction in 10 patients with axillary hidradenitis suppurativa stages II or III. All patients were assessed for surgical complications pursuant to the classification of Clavien-Dindo, subjective aesthetic results, recurrence rate, and maximum abduction angle evaluated by measuring the range of motion. All flaps healed without major or partial flap necrosis. In 12 out of 13 flaps, the aesthetic result was rated very good or good.Only one patient complained of a visible scar, but rated the overall result as satisfactory. The range of motion in the shoulder was unlimited in all cases with a maximum abduction angle of 178.8 ± 4.2°. Recurrence was not observed in any case during the postsurgical follow-up of 27.2 ± 14.4 months. The use of the two perforator-based fasciocutaneous flaps of the thoraco dorsal artery and the lateral thoracic artery offers a useful and reliable option for the reconstruction of large axillary defects while maintaining full shoulder movement and providing cosmetically satisfactory results.

Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan.

BACKGROUND: In 2016, World Health Organization guidelines conditionally recommended standardised shorter 9-12-month regimens for multidrug-resistant (MDR) tuberculosis (TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan. METHODS: Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between September 1, 2013 and March 31, 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion. RESULTS: Of 146 enrolled patients, 128 were included: 67 female (52.3%), median age 30.1 (interquartile range 23.8-44.4) years. At the end of treatment, 71.9% (92 out of 128) of patients achieved treatment success, with 68% (87 out of 128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failures with fluoroquinolone-resistance amplification in 8 patients (8 out of 22, 36.4%); 12 (9.4%) lost to follow-up; and 2 (1.5%) deaths. Recurrence occurred in one patient. Fourteen patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (adjusted OR 6.13, 95% CI 2.01; 18.63) and adherence <95% (adjusted OR 5.33, 95% CI 1.73; 16.36) were associated with unsuccessful outcome in multivariable logistic regression. CONCLUSIONS: Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of drug susceptibility testing-confirmed susceptibility.

Atmospheric sulfur and nitrogen deposition in the Athabasca oil sands region is correlated with foliar nutrient levels and soil chemical properties.

The oil extraction industry and human activity in north eastern Alberta has been growing steadily since the 1960's and is a source of air pollution. In the late 1990's the Wood Buffalo Environmental Association was established to monitor air quality for both public and environmental health. A primary environmental concern was soil acidification caused by sulfur (S) and nitrogen (N) deposition. A network of forest health monitoring (FHM) sites was established in dry jack pine ecosystems to serve as an early indicator of negative impacts. A sampling campaign was executed in 2011 and this study examines soil properties and foliar nutrients in the context of measured and modeled acid deposition. Total N (TN), SO42-, pH, base cation to aluminum ratio (BC:Al), and base saturation (% BS) are reported for the organic layer (LFH) and 3 depths in the mineral soil, while foliar nutrients were analysed from current annual growth in jack pine needles. Atmospheric deposition of S, N, BC, and potential acid input (PAI) in the study area was recently provided by Edgerton et al. (2020) and soil and foliar chemistry was evaluated based on deposition estimates and measurements. Inverse distance weighting was used to examine spatial patterns and regression analysis was used to quantify relationships between variables. The results indicated that S deposition is spatially correlated with foliar SO42- concentration, and LFH SO42-, but not mineral topsoil (0-5 cm) SO42-. Nitrogen deposition was spatially correlated with foliar N concentration, but not LFH or topsoil TN indicating potential uptake by the foliage or rapid uptake by roots in the LFH layer. High BC deposition in the same areas with the highest potential acid inputs (PAI) did not correlate significantly with changes in soil pH. However, LFH pH was significantly related to dry NH3 deposition, which has not been reported previously and requires further investigation.

Hydrological dataset of a sub-humid continental plain basin (Buenos Aires, Argentina).

The Chaco-Pampean Plain (Argentina) is the strongest economic region and the most inhabited in the country, comprising approximately 66% of the country's population (26,500 million) [1]. In this region, surface slopes are very low (<0.1%) and due to the current climatological features, floods and droughts alternate over time. Salinity and alkalinity of water and soil increase towards the flattest sector of the basin, as well as the contents of arsenic and fluoride, which restrict their human use. Worldwide, population growth and global warming, in addition to political decisions, are leading to abrupt land use changes. Under this premise, identifying and quantifying the hydrological processes that control water quantity and its chemical quality become an imperative task [2]. This data article provides a long-term hydrological dataset from a sector of the Chaco-Pampean Plain, the Del Azul creek basin. Hydrological data such as flow rates and piezometric levels, and physical-chemical (i.e., major and minor solutes, and trace elements) and isotopic (δ18O, δ2H; and d-excess) data from rainwater, surface (creek and wetland) and groundwater (at two depths) are available. Rainwater samples are derived from three precipitation collectors installed at different altitudes (monitoring period: 2010-2019; n = 57). Surface water samples were collected at three sampling sites located along the Del Azul Creek and six wetlands (monitoring period: 2018-2019; n = 12). Groundwater samples were collected from 17 piezometers with depths ranging between 3 and 10 m, and from 12 piezometers of 30 m depth, all located throughout the entire basin (monitoring period: 2018-2019; n = 115). Sampling campaigns were performed during the austral dry (summer) and wet (spring) seasons. This dataset provides useful information to understand a) how water moves from recharge to discharge areas, b) how water acquires salinity, and c) how particular solutes of concern, such as arsenic and fluoride, are distributed in space and time across in an extensive plain.

Matrix metalloproteinase 19 regulates insulin-like growth factor-mediated proliferation, migration, and adhesion in human keratinocytes through proteolysis of insulin-like growth factor binding protein-3.

Unlike most other matrix metalloproteinases (MMPs) MMP-19 is expressed in undifferentiated basal keratinocytes of healthy human skin. The human keratinocyte cell line HaCaT, which like basal keratinocytes constitutively expresses MMP-19, down-regulated the expression of MMP-19 at high calcium concentrations. Calcium-regulation occurred through E-cadherin mediated cell-cell contacts because neutralizing anti-E-cadherin antibodies restored MMP-19 expression in high calcium. Overexpression of MMP-19 in HaCaT cells (HaCaT-WT) increased cellular proliferation, as well as migration and adhesion on type I collagen. This was due to proteolysis of the insulin-like growth factor (IGF) binding protein-3 by MMP-19, which augmented signaling through the IGF-I receptor, as evidenced by its increased autophosphorylation. Conversely, these effects were not observed in cells transfected with MMP-2 or a catalytically inactive MMP-19 mutant. As further proof that increased IGF-signaling promoted adhesion and migration in HaCaT-WT cells, we reproduced these effects by treating parental HaCaT with IGF-I. We observed dephosphorylation of the focal adhesion kinase in HaCaT-WT as well as IGF-I-treated HaCaT cells, suggesting that inactivating focal adhesion kinase is a mechanism by which IGF-I enhances adhesion. Furthermore, IGF-I-triggered motility on type I collagen was mediated by MMP activity, which, however, was distinct from MMP-19. Considering the coexpression of IGFBP-3 and MMP-19 in the skin, we conclude that MMP-19 is a likely candidate to be the major IGFBP-3 degrading MMP in the quiescent epidermis. This activity might have widespread consequences for the behavior of epidermal keratinocytes.

Matrix metalloproteinase-19 expression in normal and diseased skin: dysregulation by epidermal proliferation.

Most of the matrix metalloproteinases (MMP) are not expressed in normal intact skin but they are upregulated in inflamed or diseased skin. The recently cloned MMP-19 is one of the few MMP members that are also expressed in healthy epidermis. In this study, we found that MMP-19 is generally coexpressed with cytokeratin 14 that is confined to keratinocytes of the stratum basale. MMP-19 was also detected in hair follicles, sebaceous glands, and eccrine sweat glands. Its expression, however, changed in cutaneous diseases exhibiting increased alternations of epidermal proliferation, such as psoriasis, eczema, and tinea. In the affected area, MMP-19 was also found in suprabasal and spinous epidermal layers. We also studied the regulation of MMP-19 expression at the protein level, as well as by using a promoter assay. The constitutive expression of MMP-19 was upregulated with phorbol myristate acetate and downregulated with retinoic acid and dexamethasone. Tumor necrosis factor-alpha, interleukin (IL)-6, TGF-beta, IL-15, IL-8, and RANTES as well as the bacterial compounds lipopolysaccharide and lipoteichoic acid did not show any profound effect in HaCaT cells. In contrast, type IV and type I collagens upregulated MMP-19 significantly. The dysregulation of MMP-19 expression in epidermis suggests its possible involvement in the perpetuation of cutaneous infections and proliferative disorders such as psoriasis.

The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10.

The novel CXC-chemokine ligand 16 (CXCL16) functions as transmembrane adhesion molecule on the surface of APCs and as a soluble chemoattractant for activated T cells. In this study, we elucidate the mechanism responsible for the conversion of the transmembrane molecule into a soluble chemokine and provide evidence for the expression and shedding of CXCL16 by fibroblasts and vascular cells. By transfection of human and murine CXCL16 in different cell lines, we show that soluble CXCL16 is constitutively generated by proteolytic cleavage of transmembrane CXCL16 resulting in reduced surface expression of the transmembrane molecule. Inhibition experiments with selective hydroxamate inhibitors against the disintegrin-like metalloproteinases a disintegrin and metalloproteinase domain (ADAM)10 and ADAM17 suggest that ADAM10, but not ADAM17, is involved in constitutive CXCL16 cleavage. In addition, the constitutive cleavage of transfected human CXCL16 was markedly reduced in embryonic fibroblasts generated from ADAM10-deficient mice. By induction of murine CXCL16 in ADAM10-deficient fibroblasts with IFN-gamma and TNF-alpha, we show that endogenous ADAM10 is indeed involved in the release of endogenous CXCL16. Finally, the shedding of endogenous CXCL16 could be reconstituted by retransfection of ADAM10-deficient cells with ADAM10. Analyzing the expression and release of CXCXL16 by cultured vascular cells, we found that IFN-gamma and TNF-alpha synergize to induce CXCL16 mRNA. The constitutive shedding of CXCL16 from the endothelial cell surface is blocked by inhibitors of ADAM10 and is independent of additional inhibition of ADAM17. Hence, during inflammation in the vasculature, ADAM10 may act as a CXCL16 sheddase and thereby finely control the expression and function of CXCL16 in the inflamed tissue.