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Blistering diseases bullae [keywords]
- [Repair of finger soft tissue defect with island flap based on vascular chain of cutaneous branch of dorsal metacarpal artery]. [English Abstract, Journal Article]
- Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2013 Apr; 27(4):440-2.
To investigate the operative procedure and the clinical results of the island flap based on the vascular chain of the cutaneous branch of dorsal metacarpal artery for repairing finger soft tissue defect.Between January 2008 and March 2012, 28 cases of tissue defect of fingers (32 fingers) were repaired with the island flaps based on the vascular chain of the cutaneous branch of dorsal metacarpal artery. There were 20 males (23 fingers) and 8 females (9 fingers), with an average age of 29.5 years (range, 14-67 years). The injury causes included 14 cases of crush injury, 6 cases of pressing injury, 5 cases of cutting injury, and 3 cases of avulsion injury. The locations included 10 index fingers, 13 long fingers, 6 ring fingers, and 3 little fingers. There were 9 defects of proximal segment, 12 defects of middle segment, and 11 defects of distal segment. The area of defect ranged from 1.0 cm x 0.8 cm to 5.2 cm x 3.5 cm. The disease duration was 1 hour to 15 days. The area of flaps ranged from 1.2 cm x 1.0 cm to 5.5 cm x 3.8 cm. The donors were closed by suture or were repaired with skin graft.Tense blister occurred in 3 cases, which was cured after dressing change; the other flaps survived. Wound obtained primary healing. Twenty-five patients (27 fingers) were followed up 6-25 months (mean, 16.8 months). The flaps had soft texture and satisfactory appearance. Two point discrimination was 6-9 mm (mean, 7.7 mm) at 6 months after operation. The total active movement of fingers was 105-230 degrees (mean, 204.6 degrees). The results were excellent in 17 fingers, good in 8 fingers, and fair in 2 fingers with an excellent and good rate of 92.6%.The island flap based on the vascular chain of the cutaneous branch of dorsal metacarpal artery has the advantages of the deverting point from the dorsal point to the palm, the extended vessel pedicle, and expanded operation indications, so it is not necessary to cut the dorsal metacarpal artery. It can be used to repair finger tissue defect.
- New therapies to reduce low-density lipoprotein cholesterol. [Journal Article]
- Curr Opin Cardiol 2013 Jul; 28(4):452-7.
Lipid-lowering is an intervention that reduces atherosclerosis and its complications. Statins currently form the standard of care but are not able to reduce low-density lipoprotein cholesterol (LDL-C) adequately in all patients - particularly those with familial hypercholesterolaemia and those with statin intolerance.Combination therapy with statins is well established and ezetimibe is often used as an additional LDL-C-lowering agent reducing LDL-C by 20%. However, its clinical efficacy still remains controversial. Newer, more potent methods of LDL-C reduction are in development. Both lomitapide, a microsomal transfer protein inhibitor (MTPI), and mipomersen, an antisense oligonucleotide (ASO), have been shown to improve LDL-C levels by 25-50% in patients with homozygous familial hypercholesterolaemia. In patients with heterozygous familial hypercholesterolaemia or statin intolerance antibody-based inhibitors of preprotein convertase subtilisin/kexin 9 (PCSK9) produce reductions in LDL-C of 30-65%. Cholesterol ester transfer protein inhibitors (CETPIs) reduce LDL-C by 30-40% as well as raising levels of high-density lipoprotein cholesterol (HDL-C) and may also have a role as additional LDL-C-reducing drugs.Surrogate outcome trials will be required with lomitapide or mipomersen to confirm their effects in homozygous familial hypercholesterolaemia and clinical endpoint trials will be needed for PCSK9 and CETPIs if these are to be used widely.
- Rat Model for Dominant Dystrophic Epidermolysis Bullosa: Glycine Substitution Reduces Collagen VII Stability and Shows Gene-Dosage Effect. [Journal Article]
- PLoS One 2013; 8(5):e64243.
Dystrophic epidermolysis bullosa, a severely disabling hereditary skin fragility disorder, is caused by mutations in the gene coding for collagen VII, a specialized adhesion component of the dermal-epidermal junction zone. Both recessive and dominant forms are known; the latter account for about 40% of cases. Patients with dominant dystrophic epidermolysis bullosa exhibit a spectrum of symptoms ranging from mild localized to generalized skin manifestations. Individuals with the same mutation can display substantial phenotypic variance, emphasizing the role of modifying genes in this disorder. The etiology of dystrophic epidermolysis bullosa has been known for around two decades; however, important pathogenetic questions such as involvement of modifier genes remain unanswered and a causative therapy has yet to be developed. Much of the failure to make progress in these areas is due to the lack of suitable animal models that capture all aspects of this complex monogenetic disorder. Here, we report the first rat model of dominant dystrophic epidermolysis bullosa. Affected rats carry a spontaneous glycine to aspartic acid substitution, p.G1867D, within the main structural domain of collagen VII. This confers dominant-negative interference of protein folding and decreases the stability of mutant collagen VII molecules and their polymers, the anchoring fibrils. The phenotype comprises fragile and blister-prone skin, scarring and nail dystrophy. The model recapitulates all signs of the human disease with complete penetrance. Homozygous carriers of the mutation are more severely affected than heterozygous ones, demonstrating for the first time a gene-dosage effect of mutated alleles in dystrophic epidermolysis bullosa. This novel viable and workable animal model for dominant dystrophic epidermolysis bullosa will be valuable for addressing molecular disease mechanisms, effects of modifying genes, and development of novel molecular therapies for patients with dominantly transmitted skin disease.
- Serum levels of high mobility group box 1 correlate with disease severity in recessive dystrophic epidermolysis bullosa. [Letter]
- Exp Dermatol 2013 Jun; 22(6):433-5.
In the inherited blistering skin disease, recessive dystrophic epidermolysis bullosa (RDEB), there is clinical heterogeneity with variable scarring and susceptibility to malignancy. Currently, however, there are few biochemical markers of tissue inflammation or disease progression. We assessed whether the non-histone nuclear protein, high mobility group box 1 (HMGB1), which is released from necrotic cells (including keratinocytes in blister roofs), might be elevated in RDEB and whether this correlates with disease severity. We measured serum HMGB1 by ELISA in 26 RDEB individuals (median 21.0 ng/ml, range 3.6-54.9 ng/ml) and 23 healthy controls (median 3.6, range 3.4-5.9 ng/ml) and scored RDEB severity using the Birmingham Epidermolysis Bullosa Severity Score (BEBSS; mean 34/100, range 8-82). There was a positive relationship between the BEBSS and HMGB1 levels (r = 0.54, P = 0.004). This study indicates that serum HMGB1 levels may represent a new biomarker reflecting disease severity in RDEB.
- Bullous pemphigoid with prominent milium formation. [Journal Article]
- Acta Dermatovenerol Croat 2013 May; 21(1):35-8.
Milia are very common superficial keratinous cysts, clinically seen as pearly white dome-shaped lesions with a diameter of 1-2 mm. Bullous pemphigoid (BP) is an autoimmune bullous disease characterized clinically by tense bullae on the extremities and trunk. The major target autoantigens of BP are BP180 and BP230. We report a 55-year-old Polish BP patient presenting prominent milium formation. Physical examination revealed multiple tense bullae on the erythemas scattered on the extremities and trunk. Histopathology revealed subepidermal blisters with infiltration of eosinophils in and around the blister. Direct immunofluorescence showed IgG and C3 depositions at basement membrane zone. Although indirect immunofluorescence of normal human skin sections was negative, indirect immunofluorescence of salt-split skin sections showed IgG reactivity with epidermal side. Immunoblotting showed that IgG antibodies in the serum reacted with recombinant protein of the BP180 NC16a domain. ELISA of BP180, but not BP230 and type VII collagen, showed positive results. Several months after oral prednisolone therapy, multiple large milia appeared on the healed BP lesions. Histopathology showed cysts with flaky keratinous inclusions in the mid-dermis. We diagnosed the patient as BP with milia. Since milia are occasionally found in BP, they are not a definite differential criterion from epidermolysis bullosa acquisita.
- Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties. [JOURNAL ARTICLE]
- Mol Cell Proteomics 2013 May 8.
Altered plasma neutrophil microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Herein, we investigate the proteome of neutrophil microparticles in order to shed light on their biological actions. Stimulation of human neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >400 distinct proteins with only 223 being shared by the two subsets. For instance, post-adherent microparticles were enriched in alpha-2 macroglobulin and ceruloplasmin, whereas microparticles produced by neutrophils in suspension were abundant in heat shock 70kDa protein 1. Annexin A1 and lactotransferrin were expressed in both microparticle subsets. We next determined relative abundance of these proteins in three types of human microparticle samples: healthy volunteer plasma, plasma of septic patients and skin blister exudates finding that these proteins were differentially expressed on neutrophil microparticles from these samples reflecting in part the expression profiles we found in vitro. Functional assessment of the neutrophil microparticles subsets demonstrated that in response to direct stimulation neutrophil microparticles produced reactive oxygen species and leukotriene B4 as well as locomoted towards a chemotactic gradient. Finally, we investigated the actions of the two neutrophil microparticles subsets described herein on target cell responses. Microarray analysis with human primary endothelial cells incubated with either microparticle subset revealed a discrete modulation of endothelial cell gene expression profile. These findings demonstrate that neutrophil microparticles are heterogenous and can deliver packaged information propagating the activation status of the parent cell, potentially exerting novel and fundamental roles both under homeostatic and disease conditions.
- MAPKAP kinase 2 (MK2)-dependent and independent models of blister formation in pemphigus vulgaris. [JOURNAL ARTICLE]
- J Invest Dermatol 2013 May 8.
Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by autoantibodies to the keratinocyte adhesion protein desmoglein (Dsg) 3. Previous studies suggest that PV pathogenesis involves p38 mitogen activated protein kinase-dependent and -independent pathways. However, p38 is a difficult protein to study and therapeutically target because it has four isoforms and multiple downstream effectors. In the current study, we identify MAPKAP kinase 2 (MK2) as a downstream effector of p38 signaling in PV and describe MK2-dependent and -independent mechanisms of blister formation using passive transfer of human anti-Dsg IgG4 mAbs to neonatal mice. In human keratinocytes, PV mAbs activate MK2 in a dose-dependent manner. MK2 is also activated in human pemphigus skin blisters, causing translocation of MK2 from the nucleus to the cytosol. Small molecule inhibition of MK2 and silencing of MK2 expression block PV mAb-induced Dsg3 endocytosis in human keratinocytes. Additionally, small molecule inhibition and genetic deletion of p38α and MK2 inhibit spontaneous, but not induced, suprabasal blisters by PV mAbs in mouse passive transfer models. Collectively, these data suggest that MK2 is a key downstream effector of p38 that can modulate PV autoantibody pathogenicity. MK2 inhibition may be a valuable adjunctive therapy for control of pemphigus blistering.Journal of Investigative Dermatology accepted article preview online, 8 May 2013; doi:10.1038/jid.2013.224.
- Bullous pemphigoid: role of complement and mechanisms for blister formation within the lamina lucida. [Journal Article]
- Exp Dermatol 2013 Jun; 22(6):381-5.
Bullous pemphigoid (BP), an autoimmune subepidermal blistering skin disease, demonstrates tense blisters with or without widespread erythema, blistering along the lamina lucida, immunoglobulin G and/or complement deposits at the basement membrane zone, and the presence of circulating autoantibodies against hemidesmosomal molecules. These autoantibodies usually react against 180-kDa and/or 230-kDa proteins, designated as BP180 and BP230, respectively. The precise blistering mechanisms after autoantibodies bind to antigens are not fully understood. Immune complexes are thought to initially activate the complement cascade, which may induce activation of proteases and/or cytokines and cause dermal-epidermal separation. However, why does separation run specifically within the lamina lucida in a space as narrow as 500 nm wide? This review mainly focuses on the possible mechanisms of BP-specific blistering and how separation occurs along the lamina lucida, based on existing evidence.
- Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. [Journal Article]
- J Allergy Clin Immunol 2013 Jun; 131(6):1586-93.
Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes.Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease.Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined.The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis.STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo.
- Acute blistering diseases on the burn ward: Beyond Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. [JOURNAL ARTICLE]
- Burns 2013 Apr 15.