Pressure ulcer induced by discontinuation of levodopa: Case report of an older patient with Parkinson's disease.

We report the case of a pressure ulcer that developed consequent to the discontinuation of levodopa (L-3,4-dihydroxyphenylalanine) administration. The 86-year-old female patient had a 5-year history of Parkinson's disease treated with levodopa. She developed a sacral pressure ulcer due to unanticipated immobilization induced by the discontinuation of levodopa. Discontinuation of mandatory drugs is therefore a risk factor for the development of pressure ulcers in patients with Parkinson's disease.

Backrest elevation in the semi-lateral position: Case of a sacral pressure ulcer with undermining formation.

Backrest elevation for a patient with a sacral-coccygeal pressure ulcer is necessary in certain situations, particularly to enable the patient to take meals. Deep pressure ulcers with undermining formations affect patients and create challenges for caregivers. The procedure of backrest elevation potentially worsens the pre-existing sacral-coccygeal pressure ulcers with undermining formations. Here, we report a Case of the clinical care of a patient using a simple approach for backrest elevation that minimizes additional injury to the existing sacral pressure ulcer covered with granulation tissue. In this case, we performed the backrest elevation in the semi-lateral position. After the backrest elevation, the patient was repositioned to the supine position to take a meal. The supine position was allowed at any time except during backrest elevation. The pressure ulcer of the patient improved rapidly using the combined treatment of our positioning approach and appropriate topical ointments. This practical approach may be effective for some patients as it potentially decreases the effect of shear force. The rationale for this approach can be explained by the mechanism of the undermining formation outlined in our experimental study using a pressure ulcer model mounted to a phantom. Although we used this position for patients with sacral-coccygeal pressure ulcers, this simple approach may also be considered for other patients based on our proposed pathogenesis of undermining formations.

Wound, pressure ulcer and burn guidelines - 1: Guidelines for wounds in general, second edition.

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition.

Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition.

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created.

The mechanism of persistent undermining of a sacral pressure ulcer: Experimental analyses using a deformable model and examination of skin mobility over different anatomical locations.

Undermining is an important issue in the treatment and care of deep pressure ulcers. The frequency of the undermining over different bony prominences varies. In particular, deep pressure ulcers over the sacrum exhibit undermining more frequently than those occurring over the heel. Although shear force has been suggested as a critical factor in undermining, the exact mechanism remains unclear due to ethical and technical reasons in clinical practice. To clarify this issue, a deformable model was constructed to recreate the physical and morphological properties of a pressure ulcer with persistent undermining. The model was constructed using urethane to recreate the physical properties of a pressure ulcer. To examine the clinical relevance of the model, mechanical properties of the skin and the model were measured using a durometer. The model was further mounted onto a phantom that was laid on a bed. Backrest elevation of the bed induced deformities in the urethane model, suggesting a mechanism of persistent undermining of the sacral pressure ulcer. Moreover, a simple palpation examination in elderly volunteers revealed that the skin over the sacrum was more mobile than the skin over the heel. Therefore, persistent undermining is likely caused by specific external forces and the characteristic skin mobility of the sacral region. These two different factors explain the frequent undermining that occurs in sacral pressure ulcers.

Wound, pressure ulcer and burn guidelines - 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.

Two cases of pressure ulcers related to acute calcium pyrophosphate crystal arthritis: A new concept of "disease-specific unexpected external forces".

Sudden-onset immobilisation generates unexpected external forces over bony prominences and is a potential cause of pressure ulcers. Here, we report two cases of deep pressure ulcers in patients with acute monoarthritis as a result of calcium pyrophosphate (CPP) crystal deposition (pseudogout). The patients were women in their 80 who could perform activities of daily living by themselves. They developed pressure ulcers while living in their own home. Because acute CPP crystal arthritis is known to develop in relatively healthy elderly patients, patients and caregivers do not expect sudden-onset immobilisation. In addition, larger joints are preferentially involved in acute CPP crystal arthritis, leading to the inability of patients to change positions themselves. Therefore, acute CPP crystal arthritis should be recognised as a potential causal disease for pressure ulcers. This case report further highlights a new concept of "disease-specific unexpected external force", which is beneficial for the prevention of pressure ulcers.

Polypoid granulation tissue in pressure ulcers: Significance of describing individual ulcers.

Granulation tissue formation is required for the healing of deep pressure ulcers. The wound healing process is often delayed at the stage of granulation tissue formation. The pathogenesis of pressure ulcers showing granulation tissue may vary; however, no terminology has been defined to describe existing ulcers. Thus, we previously defined terminology for granulation tissue to describe individual ulcers. Based on these terms, we retrospectively evaluated the findings of deep pressure ulcers. In particular, we focused on polypoid granular tissue, a unique morphological feature. Polypoid granulation tissues were frequently observed in pressure ulcers over the sacrum compared with those over the foot. Chronological observation of a few cases indicated that external forces from specific directions during the healing process caused the development of polypoid granulation tissue. In addition, most pressure ulcers showing polypoid granulation tissue exhibited a trench-like appearance in individual wounds. Based on these observations, polypoid granulation tissue may generate from specific external forces, which lead to wound deformity. Morphological findings in an individual wound may be useful to predict the mechanical factors on existing pressure ulcers.

Ointment vehicles regulate the wound-healing process by modifying the hyaluronan-rich matrix.

Topical ointment consists of an active ingredient and vehicle, and the vehicle largely comprises the volume of the ointment. During the treatment of chronic wounds, such as pressure ulcers, the vehicle has been considered inactive, only serving as a carrier of the main pharmaceutical. However, recent reports have indicated that the vehicle has distinct clinical effects that depend on its physicochemical properties. Therefore, an understanding of the action mechanism of the ointment vehicle in wound tissue is necessary. In this study, we established a mouse model to analyze tissue reactions induced by the following ointment vehicles, an oil-in-water emulsion (EM) vehicle; a macrogol ointment (MO), which is a water-soluble, hydrophilic vehicle; and a MOs containing sucrose (MS). EM-treated wounds exhibited an inflammatory reaction characterized by tissue edema and thick granulation tissue; however, MO- and MS-treated wounds did not exhibit this reaction. Moreover, EM-treated wounds exhibited infiltration of inflammatory cells unlike MO-treated wounds. In contrast, the formation of collagenous tissue was dominantly observed in MO-treated wounds. Because the vehicle regulates the water environment of the wound, the water-holding extracellular matrix molecules, including hyaluronan (HA) and proteoglycan, were examined using immunohistochemical and biochemical methods. The versican G1 fragment, serum-derived HA-associated protein (SHAP) and HA (the VG1F-SHAP-HA) complex characteristically found in inflammatory conditions of pressure ulcers was found in EM-treated wounds. To histologically analyze the mechanism of action of the vehicle, we evaluated the ointment vehicle-wound tissue interface in an en bloc manner. Formation of the HA-containing complex was observed locally between the vehicle and wound surface. On the basis of these data, ointment vehicles regulate the wound-healing process through the formation of HA-rich extracellular matrices at the ointment-wound interface. This study provides a better understanding of the treatment of deep-pressure ulcers with focus on ointment vehicles.

The Versican G1 Fragment and Serum-Derived Hyaluronan-Associated Proteins Interact and Form a Complex in Granulation Tissue of Pressure Ulcers.

The hyaluronan (HA)-rich extracellular matrix plays dynamic roles during tissue remodeling. Versican and serum-derived HA-associated protein (SHAP), corresponding to the heavy chains of inter-α-trypsin inhibitor, are major HA-binding molecules in remodeling processes, such as wound healing. Versican G1-domain fragment (VG1F) is generated by proteolysis and is present in either remodeling tissues or the mature dermis. However, the macrocomplex formation of VG1F has not been clarified. Therefore, we examined the VG1F-containing macrocomplex in pressure ulcers characterized by chronic refractory wounds. VG1F colocalized with SHAP-HA in specific regions of the granulation tissue but not with fibrillin-1. A unique VG1F-SHAP-HA complex was isolated from granulation tissues using gel filtration chromatography and subsequent cesium chloride-gradient ultracentrifugation under dissociating conditions. Consistent with this molecular composition, recombinant versican G1, but not versican G3, interacted with the two heavy chains of inter-α-trypsin inhibitor. The addition of recombinant VG1 in fibroblast cultures enhanced VG1F-SHAP-HA complex deposition in the pericellular extracellular matrix. Comparison with other VG1F-containing macrocomplexes, including dermal VG1F aggregates, versican-bound microfibrils, and intact versican, highlighted the tissue-specific organization of HA-rich extracellular matrix formation containing versican and SHAP. The VG1F-SHAP-HA complex was specifically detected in the edematous granulation tissues of human pressure ulcers and in inflamed stages in a mouse model of moist would healing, suggesting that the complex provides an HA-rich matrix suitable for inflammatory reactions.

Versican A-subdomain is required for its adequate function in dermal development.

Versican, a large chondroitin sulfate (CS) proteoglycan, serves as a structural macromolecule of the extracellular matrix (ECM) and regulates cell behavior. We determined the function of versican in dermal development using VcanΔ3/Δ3 mutant mice expressing versican with deleted A-subdomain of the N-terminal G1 domain. The mutant versican showed a decreased hyaluronan (HA)-binding ability and failed to accumulate in the ECM. In the early developmental stage, VcanΔ3/Δ3 dermis showed a decrease in versican expression as compared with WT. As development proceeded, versican expression further decreased to a barely detectable level, and VcanΔ3/Δ3 mice died at the neonatal period (P0). At P0, VcanΔ3/Δ3 dermis exhibited an impaired ECM structure and decreased cell density. While the level of collagen deposition was similar in both genotypes, collagen biosynthesis significantly decreased in VcanΔ3/Δ3 fibroblasts as compared with that in wild type (WT). Transforming growth factor ß (TGFß) signaling mediated through the Smad2/3-dependent pathway was down-regulated in VcanΔ3/Δ3 fibroblasts and a reduced TGFß storage in the ECM was observed. Microarray analysis revealed a decrease in the expression levels of transcription factors, early growth response (Egr) 2 and 4, which act downstream of TGFß signaling. Thus, our results suggest that A-subdomain is necessary for adequate versican expression in dermis and that versican is involved in the formation of the ECM and regulation of TGFß signaling.

A Rho-Associated Kinase Inhibitor Protects Permeability in a Cell Culture Model of Ocular Disease, and Reduces Aqueous Flare in Anterior Uveitis.

PURPOSE: Recent clinical and experimental studies have reported favorable results when using Rho-associated kinase (ROCK) inhibitors for ocular disease, and in cell culture. Disruption of the human, nonpigmented ciliary epithelial cells (HNPCECs) that comprise the blood-aqueous barrier (BAB) induces anterior uveitis; these cells therefore provide a useful cell model of ocular disease. In this study, we examined the effects of ROCK inhibitors in anterior uveitis and in HNPCECs. METHODS: Aqueous flare values and intraocular pressures (IOPs) were determined in patients with anterior uveitis, 2 weeks after administration of ripasudil hydrochloride hydrate, a commercial ROCK inhibitor used to treat glaucoma or ocular hypertension. We also investigated the effects of Y-27632, a second ROCK inhibitor, in HNPCECs following exposure to matrix metalloproteinases (MMPs) and human tumor necrosis factor-alpha (TNF-α). RESULTS: Patients with anterior uveitis, glaucoma, or ocular hypertension, referred to the Aichi Medical University from February to July 2015, were enrolled. Thirty eyes from 25 outpatients were studied. Aqueous flare values and IOPs were significantly decreased 2 weeks after ripasudil hydrochloride hydrate treatment, with no adverse events. In a cultured HNPCEC monolayer, permeability was markedly increased following exposure to MMPs-1, 3, 9, and TNF-α, with these effects attenuated by exposure to Y-27632. In cultured HNPCECs, Y-27632 provoked a marked alteration in cytoskeletal morphology without a significant change in expression levels of claudin-1 and occludin. CONCLUSION: ROCK inhibitors may confer favorable effects in anterior uveitis, possibly due to a reorganized BAB, although the relevant mechanisms remain unclear.

A new concept: 'Relative position between the external force and the bony prominence' explains location-specific occurrence of superficial injury over an undermining lesion.

AIM: A pressure ulcer is localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in combination with shear. Although the external forces and bony prominences differ depending on ulcer location, the way in which these anatomical differences affect pressure ulcer development is not well studied. METHODS: To clarify the location-dependent factors for pressure ulcer development, we focused on superficial injuries that develop over an undermining lesion, which we have termed them bilayer pressure ulcers. Because it is thought that a deep pressure ulcer is caused by ischemia at the deep lesion and a shallow pressure ulcer is caused by shear force to the superficial skin, a bilayer pressure ulcer can be considered a mixed phenotype, induced by both pressure and shear force. We retrospectively examined the frequency of bilayer pressure ulcers by location in a total of 568 pressure ulcers. RESULTS: The ratio of bilayer pressure ulcers to deep pressure ulcers staged III or more was significantly larger for pressure ulcers over the sacrum. CONCLUSION: A new concept, the relative position between the external force and bony prominence, could explain the frequency and developmental mechanism of bilayer pressure ulcers. The external forces, shape of the bony prominence, and mobility of the soft tissue may be responsible for this concept.

Pressure ulcers induced by drug administration: A new concept and report of four cases in elderly patients.

Drug-induced akinesia is a potential cause of pressure ulcers. However, pressure ulcers that are caused by drug-induced akinesia are not considered an adverse drug reaction (ADR). We propose that drug-induced pressure ulcers (DIPU) are pressure ulcers that are caused by an external force that is experienced after drug administration, and we considered resolution of these ulcers after drug discontinuation to be a supportive finding. In this report, we reviewed the medical records of pressure ulcer cases from a 300-bed hospital. Among 148 patients, four patients with pressure ulcers met the criterion for DIPU. In these cases, the suspected DIPU were related to treatment with olanzapine, fluvoxamine, valproic acid, clotiazepam, triazolam and rilmazafone. These drugs were administrated to manage the patients' behavioral and psychological symptoms that accompanied dementia. The DIPU in these patients were categorized as stage IV according to the National Pressure Ulcer Advisory Panel criteria. Discontinuation of the causal drugs led to significant improvements or complete healing of the pressure ulcers, and the patients subsequently recovered their mobility. Therefore, we propose that DIPU are potential ADR that have been overlooked in clinical practice. Thus, recognition of DIPU as an ADR may be important in preventing and appropriately managing pressure ulcers among elderly patients.

Characteristic Formation of Hyaluronan-Cartilage Link Protein-Proteoglycan Complex in Salivary Gland Tumors.

Hyaluronan (HA) and its binding molecules, cartilage link protein (LP) and proteoglycan (PG), are structural components of the hydrated extracellular matrix. Because these molecules play important roles in the tumor microenvironment, we examined the distribution of HA, LP, versican, and aggrecan in salivary gland tumors using histochemical and immunohistochemical methods, including double staining. LP was present in pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) tissues, and aggrecan was absent in the malignant tumors that we investigated. LP colocalized with both HA and aggrecan in the chondromyxoid matrix of PA, suggesting the presence of a HA-LP-aggrecan complex. Furthermore, the HA-LP-versican complex could be observed in the pseudocystic space of the cribriform structures in ACC. The characteristic HA-LP-PG complex in PA and ACC might play a role in the behavior of tumors, and immunohistochemical analysis of these molecules could represent a diagnostic adjunct for salivary gland tumors.

Wound fixation for pressure ulcers: a new therapeutic concept based on the physical properties of wounds.

A pressure ulcer is defined as damage to skin and other tissues over a bony prominence caused by excess pressure. Deep pressure ulcers that develop over specific bony prominences often exhibit wound deformity, defined as a change in the 3-dimensional shape of the wound. Subsequently, the wound deformity can result in undermining formation, which is a characteristic of deep pressure ulcers. However, to date, a concept with respect to alleviating wound deformity has yet to be defined and described. To clarify the issue, we propose a new concept called "wound fixation" based on the physical properties of deep pressure ulcers with wound deformity. Wound fixation is defined here as the alleviation of wound deformity by exogenous materials. The wound fixation methods are classified as traction, anchor, and insertion based on the relation between the wound and action point by the exogenous materials. A retrospective survey of a case series showed that wound fixation was preferentially used for deep pressure ulcers at specific locations such as the sacrum, coccyx, and greater trochanter. Moreover, the methods of wound fixation were dependent on the pressure ulcer location. In conclusion, our new concept of wound fixation will be useful for the practical treatment and care of pressure ulcers. Further discussion and validation by other experts will be required to establish this concept.