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The management of systemic sclerosis (SSc) is complex, evolving, and requires a multidisciplinary approach. At diagnosis and throughout the disease course, clinical assessment and monitoring of skin involvement is vital using the modified Rodnan Skin Score, patient-reported outcomes, and new global composite scores (such as the Combined Response Index for Systemic Sclerosis, which also considers lung function). Immunomodulation is the mainstay of skin fibrosis treatment, with mycophenolate mofetil considered first line. Meanwhile vasculopathy-related manifestations (Raynaud's phenomenon, digital ulcers) and calcinosis, require general measures combined with specific pharmacologic (calcium-channel blockers, phosphodiesterase type 5 inhibitors, and prostanoids), nonpharmacologic (digital sympathectomy and botulinum toxin injections), and often multifaceted, management approaches. Patients should be screened at the time of diagnosis specifically for systemic manifestations and then regularly thereafter, with appropriate treatment. Numerous targeted therapeutic options for SSc, including skin fibrosis, are emerging and include B-cell depletion, anti-interleukin 6, Janus kinase, and transforming growth factor β inhibition. This second article in the continuing medical education series discusses these key aspects of SSc assessment and treatment, with particular focus on skin involvement. It is vital that dermatologists play a key role in the multidisciplinary approach to SSc management. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc), also referred to as systemic scleroderma or scleroderma, is a rare, complex immune-mediated connective tissue disease characterized by progressive skin fibrosis and other clinically heterogenous features. The etiopathogenesis of SSc involves vasculopathy and immune system dysregulation occurring on a permissive genetic and epigenetic background, ultimately leading to fibrosis. Recent developments in our understanding of disease-specific autoantibodies and bioinformatic analyses has led to a reconsideration of the purely clinical classification of diffuse and limited cutaneous SSc subgroups. Autoantibody profiles are predictive of skin and internal organ involvement and disease course. Early diagnosis of SSc, with commencement of disease-modifying treatment, has the potential to improve patient outcomes. In SSc, many of the clinical manifestations that present early signs of disease progression and activity are cutaneous, meaning dermatologists can and should play a key role in the diagnosis and management of this significant condition. The first article in this continuing medical education series discusses the epidemiology, clinical characteristics, and pathogenesis of SSc in adults, with an emphasis on skin manifestations, the important role of dermatologists in recognizing these, and their correlation with systemic features and disease course. [ABSTRACT FROM AUTHOR]

There is a strong rationale to develop locally-acting surgical treatments for digital ulcers (DUs) in patients with systemic sclerosis (SSc). Our aim was to examine the safety and efficacy of local surgical management for SSc-DU. A systematic literature review was carried out until to August 2022 using 7 different databases. Original research studies concerning adult patients with SSc-DUs, and local surgical treatments were analysed using the PICO framework. We included randomized controlled trials, prospective/retrospective studies, and case series (minimum of 3 patients) References were independently screened by two reviewers including assessment of the risk of bias using validated tools. Out of 899, 13eligible articles were included. Autologous fat (adipose tissue AT) grafting was the surgical modality most identified (7 studies, 1 randomized controlled double blinded trial and 6 prospective open-label single arm studies). The healing rate (HR) with autologous fat grafting (4 studies) was 66–100 %. Three studies reported autologous adipose-derived stromal vascular fraction grafting: HR of 32–60 %. Bone marrow derived cell transplantation in a single study showed 100 % healing rate over 4–24 weeks. Surgical sympathectomy was examined in 3 studies, prospective without comparator with a median healing rate of 81 %. Two surgical studies (of direct microsurgical revascularisation and microsurgical arteriolysis) showed 100 % healing of ulcers, with no complications. Several surgical approaches for SSc-DUs have demonstrated some degree of safety and effectiveness for DU healing. However, there are significant methodological issues. Future studies are warranted to rigorously investigate surgical interventions for SSc-DUs. [ABSTRACT FROM AUTHOR]

Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs. [ABSTRACT FROM AUTHOR]

Highlights • Perpendicular flow through the anode increases MFC performance by a factor of 3.2. • Biofilm growth is increased by perpendicular flow through the anode. • Simulations show an improved substrate distribution for the perpendicular flow. Abstract The performance of microbial fuel cells (MFCs) is limited by a number of factors, including metabolic activity of electroactive microorganisms and electrochemical systematic constraints, such as overpotentials at the electrodes or IR losses. Heterogeneities of substrate distribution (availability) can also strongly limit current in MFCs. In this work we investigate how mass transport can be enhanced by changing the flow configurations in MFCs, e.g. by directing the flow through a porous anode or by applying inserts and channels to anodes. Experimental results using a perpendicular flow through the anode were compared to a parallel flow setup, showing increased current output. Finite element method (FEM) simulations were used to simulate the flow profiles and substrate distribution in each setup. The simulations revealed higher average substrate concentrations for the perpendicular flow through a porous carbon fabric anode vs. a parallel flow in the bulk phase of the MFC, related to the enhancement of transport via convection in perpendicular flow. The simulated substrate distributions found for the different inlet setups could be correlated to the experimentally obtained current flow, power output and biofilm distribution. It can be concluded that the increased current output can be explained by the flow profile in the system resulting in an increased substrate distribution in the biofilm on the electrode and a hindered oxygen transport from the cathode. [ABSTRACT FROM AUTHOR]

Microbial fuel cells (MFCs) are devices generating electrical current from a wide range of organic substrates by using bacterial metabolism. Integrations of MFCs into wastewater treatment plants seem to be the most likely application of this technology. Due to the fact that the current flow in a MFC is fundamentally produced by the metabolic activity of microorganisms, it would be desirable to elucidate the capacity of the microbial systems to optimize the energy extraction processes in MFCs. In this study, the correlation between the parameters X BH (active heterotrophic biomass) and X BA (active autotrophic biomass) from the established activated sludge model number 1 (ASM1) and the measured current flow in MFCs was investigated for the first time. The simulation protocol based on ASM1 shows a good congruence between measured and simulated effluent values for the wastewater treatment plant. Comparisons between the measured current densities and the simulated concentrations of active biomass showed linear correlations at substrate pulses and at different residence times of the substrate. Therefore, it can be concluded that the model parameter X BH and X BA of the ASM1 can be used to estimate the current output of a MFC in wastewater treatment plants. The identified correlations can be used to optimize operating conditions and to generate high current outputs of the MFCs based on simulations. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted—ischemia—and then restored—reperfusion—leading to a burst of reactive oxygen species (ROS) from mitochondria. It has been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies. [ABSTRACT FROM AUTHOR]

Summary The mitochondrial membrane potential (Δψ m ) is a major determinant and indicator of cell fate, but it is not possible to assess small changes in Δψ m within cells or in vivo. To overcome this, we developed an approach that utilizes two mitochondria-targeted probes each containing a triphenylphosphonium (TPP) lipophilic cation that drives their accumulation in response to Δψ m and the plasma membrane potential (Δψ p ). One probe contains an azido moiety and the other a cyclooctyne, which react together in a concentration-dependent manner by “click” chemistry to form MitoClick. As the mitochondrial accumulation of both probes depends exponentially on Δψ m and Δψ p , the rate of MitoClick formation is exquisitely sensitive to small changes in these potentials. MitoClick accumulation can then be quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach enables assessment of subtle changes in membrane potentials within cells and in the mouse heart in vivo. [ABSTRACT FROM AUTHOR]

In bioelectrochemical systems (BESs) at least one electrode reaction is catalyzed by microorganisms or isolated enzymes. One of the existing challenges for BESs is shifting the technology towards industrial use and engineering reactor systems at adequate scales. Due to the fact that most BESs are usually deployed in the production of large-volume but low-value products (e.g., energy, fuels, and bulk chemicals), investment and operating costs must be minimized. Recent advances in reactor concepts for different BESs, in particular biofuel cells and electrosynthesis, are summarized in this review including electrode development and first applications on a technical scale. A better understanding of the impact of reactor components on the performance of the reaction system is an important step towards commercialization of BESs. [ABSTRACT FROM AUTHOR]

cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia–reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP–cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re-evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed. [ABSTRACT FROM AUTHOR]

A personal narrative is presented in which the authors discuss the advantages of cooperation between clinician scientists and basic scientists by sharing their experiences in the research and clinical departments in the U.S. and discusses the role of the Center for Molecular Medicine Cologne.

Cutaneous tissue repair aims at restoring the barrier function of the skin. To achieve this, defects need to be replaced by granulation tissue to form new connective tissue, and epithelial wound closure is required to restore the physical barrier. Different wound-healing phases are recognized, starting with an inflammation-dominated early phase giving way to granulation tissue build-up and scar remodeling after epithelial wound closure has been achieved. In the granulation tissue, mesenchymal cells are maximally activated, cells proliferate, and synthesize huge amounts of extracellular matrix. Epithelial cells also proliferate and migrate over the provisional matrix of the underlying granulation tissue, eventually closing the defect. This review focuses on the role of keratinocyte–fibroblast interactions in the wound-healing process. There is ample evidence that keratinocytes stimulate fibroblasts to synthesize growth factors, which in turn will stimulate keratinocyte proliferation in a double paracrine manner. Moreover, fibroblasts can acquire a myofibroblast phenotype under the control of keratinocytes. This depends on a finely tuned balance between a proinflammatory or a transforming growth factor (TGF)-β-dominated environment. As the phenotype of fibroblasts from different tissues or body sites becomes better defined, we may understand their individual contribution in wound healing in more detail and possibly explain different clinical outcomes.Journal of Investigative Dermatology (2007) 127, 998–1008. doi:10.1038/sj.jid.5700786 [ABSTRACT FROM AUTHOR]

In post-natal life the inflammatory response is an inevitable consequence of tissue injury. Experimental studies established the dogma that inflammation is essential to the establishment of cutaneous homeostasis following injury, and in recent years information about specific subsets of inflammatory cell lineages and the cytokine network orchestrating inflammation associated with tissue repair has increased. Recently, this dogma has been challenged, and reports have raised questions on the validity of the essential prerequisite of inflammation for efficient tissue repair. Indeed, in experimental models of repair, inflammation has been shown to delay healing and to result in increased scarring. Furthermore, chronic inflammation, a hallmark of the non-healing wound, predisposes tissue to cancer development. Thus, a more detailed understanding in mechanisms controlling the inflammatory response during repair and how inflammation directs the outcome of the healing process will serve as a significant milestone in the therapy of pathological tissue repair. In this paper, we review cellular and molecular mechanisms controlling inflammation in cutaneous tissue repair and provide a rationale for targeting the inflammatory phase in order to modulate the outcome of the healing response.Journal of Investigative Dermatology (2007) 127, 514–525. doi:10.1038/sj.jid.5700701 [ABSTRACT FROM AUTHOR]

Abstract: Wound repair involves the sequential interaction of various cell types, extracellular matrix molecules, and soluble mediators. During the past 10 years, much new information on signals controlling wound cell behavior has emerged. This knowledge has led to a number of novel therapeutic strategies. In particular, the local delivery of pluripotent growth factor molecules to the injured tissue has been intensively investigated over the past decade. Limited success of clinical trails indicates that a crucial aspect of the growth factor wound healing strategy is the effective delivery of these polypeptides to the wound site. A molecular approach in which genetically modified cells synthesize and deliver the desired growth factor in regulated fashion has been used to overcome the limitations associated with the (topical) application of recombinant growth factor proteins. We have summarized the molecular and cellular basis of repair mechanisms and their failure, and we give an overview of techniques and studies applied to gene transfer in tissue repair. [Copyright &y& Elsevier]

Background: IL-31 is produced by activated T lymphocytes, preferentially by TH2 cells. Transgenic mice overexpressing IL-31 have a phenotype resembling allergic dermatitis in human subjects. Objective: We sought to evaluate the potential importance of IL-31 in the pathogenesis of human T cell–mediated skin diseases. Methods: We analyzed total RNA taken from 149 skin biopsy specimens from patients with atopic dermatitis (AD), allergic contact dermatitis (ACD), or psoriasis in comparison with specimens taken from patients with healthy skin (n = 13) by using quantitative real-time PCR for the expression of TH1/TH2 cytokines. Results: We found statistically increased mRNA levels of IL-31 in biopsy specimens taken from patients with AD, irrespective of the severity of the disease and serum IgE levels. Moreover, IL-31 mRNA levels were strongly increased in many biopsy specimens taken from patients with ACD. However, no increased transcription of IL-31 could be detected in biopsy specimens taken from psoriatic plaques. A comparison of mRNA levels of IL-31 with TH1 or TH2 cytokines demonstrates a correlation of the expression of IL-31 with IL-4 and IL-13 but not with IFN-γ. No significant increase of IL-31 receptor mRNA could be detected in any disease, whereas the second receptor subunit of IL-31, the oncostatin M receptor, seems to be enhanced transcribed in patients with psoriasis. Conclusion: IL-31 expression is not only increased in patients with AD but also in those with ACD, 2 pruritic skin disorders. In both types of eczema, expression of IL-31 is associated with the expression of the TH2 cytokines IL-4 and IL-13. Clinical implications: IL-31 might contribute not only to the development of AD but also to ACD-provoked skin inflammation. [Copyright &y& Elsevier]

Vascular endothelial growth factor-A (VEGF-A) is a crucial mediator of vascular hyperpermeability, angiogenesis, and inflammation, processes intimately involved in tissue repair. Although much emphasis has been placed on understanding the synthesis and stability of VEGF-A mRNA, relatively little attention has been given to the study of the stability and processing of VEGF-A proteins themselves. In recent years, several studies indicated that VEGF-A protein activity is highly controlled through interaction with angiogenic or non-angiogenic mediators. We analyzed mechanisms that might control extracellular VEGF-A processing during wound repair. First, our studies provide evidence that VEGF-A protein is a target of proteases present in the microenvironment of human chronic non-healing wounds. Serine proteases, in particular plasmin cleave VEGF165 and digested VEGF fragments, showed decreased mitogenic activity. Inactivation of the plasmin cleavage site Arg110/Ala111 preserved the structural integrity and increased the angiogenic potency of VEGF165 when tested in an impaired healing mouse model. Secondly, we identified significantly increased levels of the potent VEGF-A inhibitor, the soluble form of the VEGF receptor VEGFR-1 (sVEGFR-1) in non-healing wounds when compared to healing wounds. Wound closure in healing and non-healing wounds correlated significantly with a decline in sVEGFR-1 levels. These observations support the concept that VEGF-A and VEGF-A receptors are important mediators in tissue repair. Further, our data provide mechanisms how VEGF-A-mediated interactions are disturbed during impaired healing.Journal of Investigative Dermatology Symposium Proceedings (2006) 11, 79–86. doi:10.1038/sj.jidsymp.5650016 [ABSTRACT FROM AUTHOR]

The epidermal basement membrane zone comprises various biochemical constituents, some of which may be affected or involved in certain forms of mechanobullous diseases. Recently, nidogen and a low density form of heparan sulfate proteoglycan--two ubiquitous, noncollagenous components of basement membranes--were isolated and characterized, and affinity-purified antibodies to each component were prepared. These antibodies were used to study the distribution of both antigens in normal and diseased human skin. By immunofluorescence, both nidogen and heparan sulfate proteoglycan were linearly distributed along the basement membrane of the dermal-epidermal junction, adnexal structures, and blood vessels of normal human skin. On suction-induced blisters of normal skin, both antigens were found at the base of the blister, indicating that each was within or below the lamina lucida. By indirect immunoelectron microscopy, both antigens were ultrastructurally located within the lamina densa. The staining patterns for nidogen and heparan sulfate proteoglycan were examined in 11 patients with either junctional, dominant dystrophic, or recessive dystrophic epidermolysis bullosa, and were found to be not different from the patterns observed in normal skin. [ABSTRACT FROM AUTHOR]

Sera from 101 patients with progressive systemic scleroderma were analyzed for circulating aminopropeptides of type III collagen using a radioimmunoassay which measures the intact and degraded forms (Fab assay). About 41% of the patients were found to have values above the normal range. A good correlation was observed between elevated levels of aminopropeptides and the degree of involvement of the skin and internal organs in the patients. Most patients (89%) with an active progression of the disease but not those in a stationary phase showed increased serum levels of aminopropeptides. Treatment with corticosteroids apparently normalized the levels of aminopropeptides. Only minor changes were observed with an antibody-based radioimmunoassay which measures primarily the intact form of the aminopropeptide. [ABSTRACT FROM AUTHOR]

Dermatofibrosarcoma protuberans is a low-grade malignant tumor that grows invasively but rarely forms metastases. Its origin is still controversial. We characterized the synthesis of collagen in detail in cells which were obtained from dermatofibrosarcoma protuberans tumors by enzymatic tissue disintegration. Similar to fibroblasts, all tumor cell strains produced considerable amounts of collagen. However, the rate was reduced compared to normal skin fibroblasts. Cells grown from the tumors synthesized type I collagen, but no type III could be detected. After serial passaging the cultures started to produce type III collagen, which is probably due to a slow overgrowth by normal fibroblasts. [ABSTRACT FROM AUTHOR]

The Elhers-Danlos syndrome type VI is an inherited disorder of collagen metabolism characterized by a defective lysyl hydroxylase. The resulting lack of hydroxylysine has been found in several connective tissues, all of which show varying degrees of clinical symptoms. In the present study, collagen was isolated from different connective tissues and the degree of hydroxylation of lysyl residues was determined. Subsequently, collagen types I, II, III, IV, and V have been prepared from a number of tissues. Insufficient hydroxylation of lysyl residues was found in type I and type III collagen, whereas types II, IV, and V showed normal amounts of hydroxylysine. The expression of the defect, even for type I and type III collagen, varied widely from one tissue to another. A complete lack of hydroxylysine was observed in skin, while it was less pronounced in tissues such as bone, tendon, lung, or kidney. The data suggest the presence of several isoenzymes having varying affinities to the different collagen types. [ABSTRACT FROM AUTHOR]

Skin biopsies from a patient with hyalinosis cutis et mucosae (HCM) were studied by routine histology, electron microscopy, biochemical extractions, and immunofluorescence for extracellular matrix proteins. The upper dermis consisted of large hyaline regions mainly composed of noncollagenous proteins. A portion of this material was solubilized by reduction in 8 M urea. Antisera against these proteins revealed multiple antigens most of which were also detectable in normal skin. The hyaline regions showed a reduced content of collagens, particularly of thick fibrils and of fibronectin, The basal lamina around capillaries and at the dermal-epidermal junction appeared as multiple, concentric layers of amorphous laminac intercalated with thin collagen fibrils. They consisted of collagens type III and IV and of laminin as shown by immunofluorescence, Anti-bodies could also be raised against laminin of HCM skin which showed strong cross-reactions with authentic mouse laminin. Cultured fibroblasts from the HCM lesion showed increased synthesis of noncoltagenous proteins at the expense of newly synthesized collagens, Some but not all of these noncollagenous proteins were also produced by fibroblasts from normal skin. The above data indicate that the hyaline material in HCM originates from the overproduction of noncollagenous proteins, most of which are normal constituents of human skin. [ABSTRACT FROM AUTHOR]

Laminins represent a growing family of disulfide linked heterotrimers constituted by the association of three genetically different polypeptides, the α, β, and γ chains. Laminins are endowed with structural and biological functions. They play a direct critical role in the control of cellular behavior by providing cells with specific information through interactions with cell surface receptors. Because of their structural properties, they represent crucial building blocks for tissue assembly, architecture, and stability. The expression of laminin chain variants is spatio-temporally regulated, which suggests that laminin isoforms might have different functions responsible for the biological and morphological polymorphism of basement membranes. The different cells present in the skin express several laminin chains, which lead to the deposition of various laminin isoforms, whose mechanical and biological functions are likely to be adapted to the properties of the dermo-epidermal junction. Recently, defective laminin isoforms have been shown to be associated with several inborn and acquired diseases, illustrating a major structural function for laminins in skin integrity. [ABSTRACT FROM AUTHOR]

Pustulosis acuta generalisata (PAG) is a rare poststreptococcal disease of the skin, which has been reported in children and adults after streptococcal throat infection. Herein, we report on the case of a 47-year-old woman with typical clinical and histologic findings of PAG emerging after a pharyngeal infection in whom inflammatory joint-involvement developed. The patient was found to be HLA-A2 and HLA-B35 positive. Whereas HLA-B35 might be associated with pustular skin diseases, HLA-A2 is a risk factor for the development of rheumatoid arthritis. [Copyright &y& Elsevier]

The article presents an obituary for Charles M. Lapiere , a dermatologist and cell biologist.

A 31-year-old woman had an organoid nevus characterized by multiple trichilemmal cysts arranged in a bandlike pattern. The involved streaks followed Blaschko''s lines and were covered, in addition, by multiple filiform hyperkeratoses and comedo-like plugs. Some histopathologic features of this complex nevus were reminiscent of those of well-established organoid nevi such as nevus comedonicus, porokeratotic eccrine nevus, or hair follicle nevus, but the presence of multiple large trichilemmal cysts was a conspicuously distinctive abnormality. Consequently, we propose for this new organoid nevus the names “trichilemmal cyst nevus” or “nevus trichilemmocysticus.” [Copyright &y& Elsevier]

Background: Various randomized studies evidenced that immunoadsorption (IA) repeated at monthly intervals induced acute and prolonged hemodynamic benefit in patients with severe heart failure due to dilated cardiomyopathy. Some findings indicate that the use of only one course of IA therapy may also induce prolonged beneficial effects. Methods: This randomized study included 22 patients suffering from severe heart failure (left ventricular ejection fraction [LVEF] <35%) due to dilated cardiomyopathy. The first group (11 patients) was treated with four IA courses at monthly intervals. The second group (11 patients) received one IA course only without repetition. In all patients of the 2 groups, each course was performed in one IA session on 5 consecutive days. At 3 and 6 months after the beginning of this study, left ventricular function and hemodynamics were reevaluated in both groups. Results: Immunoadsorption treatment repeated at monthly intervals induced improvement in LVEF after 6 months, that is, from 28.1% ± 1.5% to 37.0% ± 1.6% (±SEM; P < .01 vs baseline). Patients treated in only one IA course experienced comparable improvement of LVEF after 6 months, that is, from 26.5% ± 2.2% to 34.8% ± 2.9% (P < .01 vs baseline). In the group with repeated IA courses, cardiac index increased from baseline 2.2 ± 0.1 to 2.8 ± 0.2 L min−1 m−2 after 6 months (P < .01 vs baseline). In comparison, during the 6 months of this study in the group with one IA course, cardiac index increased from 2.1 ± 0.1 to 2.7 ± 0.2 L min−1 m−2. After 3 and 6 months, there were no significant differences between the 2 groups with respect to LVEF and all measured hemodynamic parameters. Conclusions: One course of IA treatment may induce improvement of left ventricular function over a period of 6 months, with results comparable to those received by IA treatment repeated at monthly intervals. [Copyright &y& Elsevier]

Radial acquisitions can suffer from trajectory errors leading to reduced image quality. Here we present a new method of trajectory correction that uses all spokes of a radial acquisition and compare it to an existing method that uses a two-spoke pre-scan calibration. For both methods, estimates of the necessary shifts were made using magnitude or phase data and the performances were compared. The additional effect of BO correction was considered in all cases. Mouse cardiac scans were used for the comparisons and we also compared the quality of navigator signals obtained from the radial data with each technique.The proposed method gave improved image quality over the existing method, as assessed by visual inspection and quantitative evaluation of artifacts. The typical shading artifacts seen in radial scans were significantly reduced with both approaches, with phase-based corrections generally outperforming magnitude-based methods. BO correction gave further improvements in each case. Furthermore, modulation of navigator signals due to the acquisition angle was significantly reduced with the new technique. We show that our proposed method works well to reduce artifacts seen in mouse cardiac imaging that can make faster imaging feasible. [ABSTRACT FROM AUTHOR]

Abstract: Heart failure originating from myocardial infarction (MI) is a leading cause of death worldwide. Mouse models of ischaemia and reperfusion injury (I/R) are used to study the effects of novel treatment strategies targeting MI, however staging disease and treatment efficacy is a challenge. Damage and recovery can be assessed on the cellular, tissue or whole-organ scale but these are rarely measured in concert. Here, for the first time, we present data showing measures of injury in infarcted mice using complementary techniques for multi-modal characterisation of the heart. We use in vivo magnetic resonance imaging (MRI) to assess heart function with cine-MRI, hindered perfusion with late gadolinium enhancement imaging and muscular function with displacement encoded with stimulated echoes (DENSE) MRI. These measures are followed by positron emission tomography (PET) with 18-F-fluorodeoxyglucose to assess cellular metabolism. We demonstrate a protocol combining each of these measures for the same animal in the same imaging session and compare how the different markers can be used to quantify cardiac recovery on different scales following injury. [Copyright &y& Elsevier]

Abstract: Reactive oxygen species (ROS) are generated by several different cellular sources, and their accumulation within the myocardium is widely considered to cause harmful oxidative stress. On the other hand, their role as second messengers has gradually emerged. The equilibrium of the nitroso/redox balance between reactive nitrogen species and ROS is crucial for the health of cardiomyocytes. This review provides a comprehensive overview of sources of oxidative stress in cardiac myocytes and describes the role of the nitroso/redox balance in cardiac pathophysiology. Although the exact mechanism of ROS production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox''s) is not completely understood, Nox2 and Nox4 have particularly important roles within the myocardium. Increasing evidence suggests that Nox2 produces superoxide and Nox4 generates only hydrogen peroxide. We also discuss the key role of nitric oxide synthases (NOSs) in the maintenance of the nitroso/redox balance: uncoupled endothelial NOS has been suggested to shift from nitric oxide to ROS production, contributing to increased oxidative stress within the myocardium. Furthermore, we highlight the importance of sequentially targeting and/or regulating the specific sources of oxidative and nitrosative stress to prevent and/or reverse myocardial dysfunction. Inhibition of NADPH oxidase-dependent ROS is considered to be a potential strategy for treatment of cardiomyopathy. Neither in vivo nor clinical data are available for NADPH oxidase inhibitors. Specifically targeting the mitochondria with the antioxidant MitoQ would be a very promising translation approach, because it could prevent mitochondrial permeability transition pore opening when ROS are produced during heart reperfusion. Enhancing NO signaling could also be a promising therapeutic approach against myocardial dysfunction. [Copyright &y& Elsevier]

Abstract: Tumor cells traverse the basement membrane zone and gain access to the underlying mesenchyme to eventually form metastases. Laminin 5 is a major component of the basement membrane and connects keratinocytes at the level of hemidesmosomes to the mesenchyme. Underneath invading tumor cells anti-laminin 5 staining is diminished, and laminin 5 degradation products can stimulate cell migration and epidermal growth factor (EGF) receptor signaling. To investigate laminin 5 expression in parental HaCaT and tumorigenic c-Ha-ras-transformed HaCaT II-4rt keratinocytes, the cells were cultivated under monolayer and organotypic culture conditions. In monolayer cultures, HaCaT and c-Ha-ras-transformed HaCaT II-4rt keratinocytes secreted comparable amounts of laminin 5. After 7 days of organotypic cultures, collagen IV, β4-integrin, nidogen and laminin 5 were detected along the epithelial–mesenchymal interface of parental HaCaT keratinocytes, while staining for these proteins was patchy or absent in the organotypic cultures with c-Ha-ras-transformed HaCaT II-4rt cells. Immunoblotting analysis confirmed absence of laminin 5 deposition in organotypic cultures of c-Ha-ras-transformed HaCaT II-4rt while the protein was detected in organotypic cultures of HaCaT keratinocytes. Surprisingly, however, the α3 and γ2 laminin chain transcripts were strongly induced in c-Ha-ras-transformed HaCaT II-4rt cells by organotypic culture conditions, indicating that invasive epidermal tumor cells retain high mRNA levels for laminin 5 chains and suggesting an autocrine/paracrine induction of the laminin chain mRNAs. Moreover, as laminin 5 was absent in organotypic cultures of c-Ha-ras-transformed HaCaT II-4rt cells, it suggests immediate degradation of the protein. Degradation products may further contribute to the malignant phenotype by enhancing cellular migration and EGF-receptor activation. [Copyright &y& Elsevier]

The role of interleukin-4 as a regulator of immune responses in the skin is investigated with regard to the outcome of contact hypersensitivity reaction in interleukin-4-deficient BALB/C mice. In previous studies conflicting results were obtained concerning the role of interleukin-4 in contact hypersensitivity reactions supporting either a proinflammatory or rather an inhibitory function of this cytokine. Interleukin-4 deficient BALB/C mice sensitized to 2,4-dinitrochlorobenzene showed after challenge a significant reduction in magnitude and duration of the contact hypersensitivity response in comparison with wild-type mice. This attenuation was accompanied by a significant reduction of edema and cellular infiltrates in the dermis and a lacking induction of IL-10 mRNA expression in skin. Also, adoptive transfer experiments revealed that BALB/C mice failed to exhibit contact hypersensitivity after injection of lymph node cells obtained from sensitized interleukin-4 deficient mice. To examine further the role of the contact allergen used to induce the contact hypersensitivity response, mice were also sensitized and challenged with Oxazolone. Here a similar magnitude and duration of contact hypersensitivity in both the interleukin-4 deficient mice and BALB/C control mice was observed. This indicates that the contact hypersensitivity response to 2,4-dinitrochlorobenzene and Oxazolone may partly evolve on different pathways being dependent and independent of interleukin-4. Our results clearly show that the complete loss of endogenous interleukin-4 expression in BALB/C mice is associated with an impaired manifestation of contact hypersensitivity response to 2,4-dinitrochlorobenzene, implying an important proinflammatory function of this cytokine. [ABSTRACT FROM AUTHOR]

Primary cultures of fibroblasts obtained from the papillary, reticular and subcutaneous layer of scleroderma skin were analyzed for protein synthesis by metabolic labeling and radioimmunoassays. Several of these cultures showed a 10- to 20-fold increase in the production of total protein and collagen as well as of fibronectin and type III procollagen as compared to cells from unaffected individuals. Most of the increases were noted in the reticular and subcutaneous layers. With cells from other patients increased synthesis was found in some of the explants or for only some of the products. The heterogeneity observed here could represent heterogeneity in the disease, in the cells studied or in the state of the disease at the time the cells were obtained. [ABSTRACT FROM AUTHOR]

Mitochondria are essential signaling organelles that regulate a broad range of cellular processes and thereby heart function. Multiple mechanisms participate in the communication between mitochondria and the nucleus that maintain cardiomyocyte homeostasis, including mitochondrial reactive oxygen species (ROS) and metabolic shifts in TCA cycle metabolite availability. An increased rate of ROS generation can cause irreversible damage to the cell and proposed to be a leading cause of many pathologies, including accelerated aging and heart disease. Myocardial impairments are also characterised by specific coordinated metabolic changes and dysregulated inflammatory responses. Hence, the mitochondrial respiratory chain is an important mediator between health and disease in the heart. This review will first outline the sources of ROS in the heart, mitochondrial metabolite dynamics, and provide an overview of their implications for heart disease. In addition, we will concentrate our discussion around current cardioprotective strategies relevant to mitochondrial ROS. Thorough understanding of mitochondrial signaling and the complex interplay with vital signaling pathways in the heart might allow us to develop novel therapeutic approaches to cardiovascular disease. [Display omitted] • Redox dependent signaling regulates cardiac physiology and disease. • TCA cycle metabolites act as messengers of cardiomyocyte homeostasis. • High concentrations of mitochondrial ROS and accumulation of TCA cycle metabolites contribute to heart failure development. • Modulating cardiac energy substrate preference and concentration of mitochondrial ROS may be promising treatment options. [ABSTRACT FROM AUTHOR]