Epidermolysis bullosa. Part 1: causes, presentation and complications

This article is the first in a series of three focusing on the causes, clinical presentation, complications and care of adult patients affected by epidermolysis bullosa (EB), a group of rare genetic skin fragility disorders. Although the condition is rare, in some cases it presents extreme challenges both to those affected and those involved in the care of the EB patient; therefore, these articles may have relevance for other long-term disorders. While there is a wealth of information regarding the 'science' of EB there is dearth of information regarding the care of the adult EB patient, and this series of articles will endeavour to fill that gap. This article focuses mainly on those patients affected with the most severe form of EB found in the adult group, recessive dystrophic epidermolysis bullosa; with the part two looking at the care of the adult with EB from the nursing perspective, including wound management, and the experiences of a specialist EB psychotherapist being presented in the final article of the series. Readers will thus have an opportunity to gain an overall view of this difficult condition.     

E-flow显像在胎儿肺静脉超声检查中的应用

目的 探讨E-flow显像技术在胎儿肺静脉超声检查中的价值。方法 以肺做透声窗,对332例不同孕周胎儿肺静脉进行检查,运用二维超声心动图(2DE)、彩色多普勒血流显像(CDFI)及E-flow显示技术检查肺静脉,对三种方法进行比较。结果 肺静脉显示情况为：孕12～22周胎儿共118例,2DE显示7例,CDFI显示49例,E-flow显示73例,E-flow显示率明显高于前两者(P＜0.001);23～40周胎儿214例,2DE显示41例,CDFI显示171例,E-flow显示177例,E-flow及CDFI显示率明显高于2DE(P＜0.001),E-flow与CDFI显示率无明显差异(P＞0.0167)。结论E-flow对肺静脉血流较敏感,在中孕早期对肺静脉的显示明显优于2DE及CDFI。     

Comparative analysis of the DNA staining efficiencies of different fluorescent dyes in preparative agarose gel electrophoresis.

Ethidium bromide (EB) is a mutagen and toxin that is widely used in the laboratory for visualization of nucleic acids. Safer nucleic acid stains, such as SYBR Gold, SYBR Green, GoldView, GeneFinder, and GoldStar, have been developed. However, there has been no systematic comparative analysis of the staining efficiencies of these dyes. In the present study, SYBR Gold, SYBR Green I, GoldView and EB were compared. Although both SYBR Gold and SYBR Green alter electrophoretic mobility and thus DNA size estimates, they are cost-effective alternatives to EB. SYBR Gold was more sensitive than SYBR Green I at detecting short fragments, but 50-bp bands were clearly visible using either dye when visualized with a long integration time. SYBR Gold or SYBR Green I are sensitive and relatively safe alternatives to EB. In our laboratory, the SYBR Gold method is now used routinely by all members of our group with great consistency and success.     

彩色多普勒超敏血流显像技术显示孕11~13+6周胎儿心脏轴

目的 探讨彩色多普勒超敏血流（HD flow）显像技术在11~13⁺⁶周胎儿心脏轴显像中的价值。方法 采用灰阶超声及彩色多普勒HD flow显像技术对197胎孕11~13⁺⁶周胎儿进行心脏轴显像,比较两种方法对不同孕周胎儿心脏轴的显示率;采用两种方法测量55胎孕13~13⁺⁶周胎儿的心脏轴值,并进行比较。结果 孕11~13⁺⁶周,灰阶超声显像和HD flow显像对心脏轴的显示率分别为67.01%（132/197）、85.28%（168/197）,差异有统计学意义（P<0.01）;孕11~11⁺⁶周,显示率分别为32.39%（23/71）、69.01%（49/71）,差异有统计学意义（P<0.01）;孕12~12⁺⁶周,显示率分别为78.26%（54/69）、92.75%（64/69）,差异有统计学意义（P<0.01）;孕13~13⁺⁶周,两种方法显示率均为96.49%（55/57）。灰阶超声显像和HD flow显像测量心脏轴值分别为（45.34±3.99）°、（43.62±3.33）°,差异有统计学意义（t=7.11,P<0.01）。灰阶超声测得数值离散度较大,HD flow显像测得数值相对集中。结论 与灰阶超声显像相比,彩色多普勒HD flow显像可提高孕11~12⁺⁶周胎儿心脏轴显示率,且可降低13~13⁺⁶周胎儿心脏轴值的测量误差。     

PC机上基于CT、MRI图像构建的颌面部三维数字模型

背景：近年来国内外学者对个人PC机上重建颌面部骨组织、皮肤、肌肉三维可视化模型进行了大量研究,但对于建立颌面部骨骼、皮肤、肌肉、血管的整体三维可视化模型尚无报道。目的：利用螺旋CT、MRI数据及三维重建软件,在普通PC机建立颌面部整体的三维可视化模型。方法：选择1名健康成年男性作为建模对象,分别通过螺旋CT、核磁共振扫描,得到样本的DICOM标准图像。将所有CT、MRI图像导入Mimics,建立颌面部骨骼、部分咀嚼肌、三叉神经池、颈内动脉、颈内静脉的三维可视化模型。选择颌面部骨骼三维模型为基准,将由MRI图像建立的肌肉、血管、三叉神经池模型导入,进行三维模型空间配准。最终得到颌面部整体的三维可视化模型。结果与结论：成功建立了颌面部骨骼、肌肉、皮肤、三叉神经池、血管的整体三维模型,准确反映了颌面部复杂的解剖结构,可为临床诊断提供可靠的解剖资料,并为今后的模拟手术打下良好的基础。     

Emergency department presentation of ‘delusional parasitosis by proxy’. Delusional parent,injured child

We report a case of 'delusional parasitosis by proxy'. A sixyear old child was brought to the emergency department by a mother with concerns that her son had a skin and scalp infestation. Despite the absence of any clinical findings being found on exam, the mother remained disproportionately concerned. Follow up care was recommended with the child's primary care. The mother returned to the ED with her child three weeks later with concerns that her son had an inflamed scalp and eyes. The mother remained insistent that the child was infested with bugs and she had sought care at two other locations where the child was prescribed permethrin on both visits. She had been applying the medication repeatedly. On exam the boy's scalp had been shaved and was erythematous and irritated; his eyebrows and eyelashes had also been shaved off and likely contributed to an irritant conjunctivitis from repeated applications of topical permethrin lotion. No evidence of infestation was identified. We recruited the assistance of the maternal grandparents, child protective services and primary care pediatrics and the child was removed from the mother's custody and placed into the custody of the grandparents. Six weeks later with basic skin care and erythromycin ophthalmic ointment for the eyes, the child's hair, eyebrows and eyelashes grew had grown in, and the scalp irritation had resolved. The mother had sought and received psychiatric care and was improving.     

BP180 gene delivery in junctional epidermolysis bullosa.

Epidermolysis bullosa (EB) comprises a family of inherited blistering skin diseases for which current therapy is only palliative. Junctional EB (JEB) involves dissociation of the dermal-epidermal junction and results from mutations in a number of genes that encode vital structural proteins, including BP180 (type XVII collagen/BPAG2). In order to develop a model of corrective gene delivery for JEB, we produced a retroviral expression vector for wild-type human BP180 and used it to restore BP180 protein expression to primary keratinocytes from BP180-negative patients with generalized atrophic JEB. Restoration of full-length BP180 protein expression was associated with adhesion parameter normalization of primary JEB keratinocytes in vitro. These cells were then used to regenerate human skin on immune-deficient mice. BP180 gene-transduced tissue demonstrated restoration of BP180 gene expression at the dermal-epidermal junction in vivo while untransduced regenerated JEB skin entirely lacked BP180 expression. These findings provide a basis for future efforts to achieve gene delivery in human EB skin tissue.     

自动四维彩色容积超声在胎儿心脏检查中的应用

目的 探讨自动四维彩色容积超声在正常胎儿心脏检查中的应用价值.方法 对120例孕中期(18～23孕周)胎儿心脏进行四维容积扫查,在显示四腔心切面、启动彩色多普勒后采集胎儿胸部容积数据,利用超声自动多平面成像法自动获取3个诊断切面,分别为切面1(左心室流出道切面)、切面2(右心室流出道切面)及切面3(动脉导管弓切面),并采用超声断层显像法(TUI)显示所有切面的彩色血流图.对所有的容积数据进行分析并确定在每个容积数据中切面1～3是否正确显示.结果 通过自动四维彩色容积超声扫描,切面1～3的显示率分别为100%、96.67%、91.67%.切面1至少可在连续3个TUI图像上可靠显示,切面2和切面3均至少可在连续2个TUI图像上可靠显示.结论 自动四维彩色容积超声可自动获取胎儿心脏检查中所需的重要切面,显示率较高,并可观察相应切面的血流情况,显示效果良好.     

高强度聚焦超声非侵入性损伤猪膀胱壁的实验研究

目的探讨高强度聚焦超声非侵入性治疗膀胱肿瘤的可行性。 方法用高强度聚焦超声对16只小型香猪膀胱各壁进行了定点辐照，观察辐照前后靶区的B超、彩超图像变化。分别于辐照后1h、4周、8周处死动物，观察靶区及膀胱周围组织肉眼、光镜及电镜变化和尿液变化。 结果高强度聚焦超声能透过皮肤特异性破坏膀胱壁靶组织，导致黏膜、黏膜下层及浅肌层组织的不可逆性损伤，B超、彩超可监测到靶区的变化，4周后损伤点逐渐修复，8周后已完全被纤维结缔组织取代。 结论高强度聚焦超声非侵入性治疗膀胱肿瘤是可行的。     

A rare case of streptomycin-induced toxic epidermal necrolysis in a patient with tuberculosis: a therapeutic dilemma

OBJECTIVE: To report a case of streptomycin-induced toxic epidermal necrolysis (TEN). CASE SUMMARY: A 55-year-old woman was admitted for treatment of active pulmonary tuberculosis (TB). She was given standard oral anti-TB chemotherapy including isoniazid, rifampin, pyrazinamide, and streptomycin. On the fourth day of therapy, she experienced high fever at 39 degrees C, chills, vomiting, pruritus, and diffuse erythema, followed by extensive bullae formation and skin denudation. Diagnosis of TEN was considered, and all anti-TB drugs were discontinued. Skin biopsy disclosed complete epidermal necrosis with dermal-epidermal cleavage and absence of inflammatory infiltrate, highly suggestive of TEN. The patient was transferred to the intensive care unit. Her general condition and skin lesions improved. A staged-fashion exposure test to the 4 anti-TB drugs allowed the incrimination of streptomycin as the offending agent. DISCUSSION: Anti-TB drugs, mainly rifampin, ethambutol, and isoniazid, have been incriminated in TEN. Streptomycin-induced TEN remains an extremely rare event. However, minor allergic skin reactions (rash, urticaria) have been described with this drug. Our patient presents a rare case of streptomycin-related TEN. Even though dangerous, a step-wise exposure test was necessary to allow safe treatment of active pulmonary TB. It also provided a strong argument of a cause-effect relationship between TEN and streptomycin. An objective causality assessment using the Naranjo rating scale revealed that the adverse drug event was highly probable. CONCLUSIONS: Streptomycin should be added to the list of drugs that induce TEN.     

Genetic linkage of type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils.

Epidermolysis bullosa (EB) in a group of genodermatoses characterized by the fragility of skin. Previous studies on the dystrophic (scarring) forms of EB have suggested abnormalities in anchoring fibrils, morphologically recognizable attachment structures that provide stability to the association of the cutaneous basement membrane to the underlying dermis. Since type VII collagen is the major component of the anchoring fibrils, we examined the genetic linkage of dominant dystrophic EB (EBDD) and the type VII collagen gene (COL7A1) locus, which we have recently mapped to chromosome 3p, in three large kindreds with abnormal anchoring fibrils. Strong genetic linkage of EBDD and COL7A1 loci was demonstrated with the maximum logarithm of odds (LOD) score of 8.77 at theta = 0. This linkage was further confirmed with two additional markers in this region of the short arm of chromosome 3, and these analyses allowed further refinement of the map locus of COL7A1. Since there were no recombinants between the COL7A1 and EBDD loci, our findings suggest that type VII collagen is the candidate gene that may harbor the mutations responsible for the EB phenotype in these three families.     

Hydrocortisone 17-butyrate (Locoid) 0.1% cream versus hydrocortisone (Uniderm) 1% cream in the treatment of children suffering from atopic dermatitis

A randomized, double-blind, left-right study to compare the therapeutic efficacy of hydrocortisone 17-butyrate (Locoid) 0.1% cream with hydrocortisone (Uniderm) 1% cream was performed in forty children suffering from atopic dermatitis. The medications were applied to symmetrical bilateral skin lesions twice daily for a maximum of 4 weeks or until complete clinical clearance of such lesions had occurred. Complete clearance of skin symptoms was found in 36% of the Locoid-treated sides and in 23% of the Uniderm-treated sides following 2 weeks of therapy and in 60% and 30%, respectively, after 4 weeks of treatment. This difference in clearance rate after 4 weeks between both preparations was significantly in favour of Locoid cream. The expressed preferences of patients/parents and investigator were also significantly in favour of Locoid cream, both after 2 and 4 weeks. No serious side-effects were reported during this study. It is concluded that Locoid cream is significantly superior to Uniderm cream in the treatment of atopic dermatitis in children.     

Maturational regulation of globotriaosylceramide, the Shiga-like toxin 1 receptor, in cultured human gut epithelial cells.

Epidermolysis bullosa (EB) is a group of heritable mechano-bullous skin diseases classified into three major categories on the basis of the level of tissue separation within the dermal-epidermal basement membrane zone. In the most severe, dystrophic (scarring) forms of EB, blisters form below the cutaneous basement membrane at the level of the anchoring fibrils, which are composed of type VII collagen. Ultrastructural observations of altered anchoring fibrils and genetic linkage to the type VII collagen locus (COL7A1) have implicated COL7A1 as the candidate gene in the dystrophic forms of EB. We have recently cloned the entire cDNA and the gene for human COL7A1. In this study, we describe distinct mutations in both COL7A1 alleles in three brothers with severe, mutilating recessive dystrophic EB (the Hallopeau-Siemens type, HS-RDEB). The patients are compound heterozygotes for two different mutations, both of which result in a premature termination codon in COL7A1, and the parents were shown to be clinically heterozygous carries of the respective mutations. Premature termination codons in both alleles of COL7A1 appear to be the underlying cause of severe, recessive dystrophic EB in this family.     

Subependymal pseudocysts in the fetal brain: prenatal diagnosis of two cases and review of the literature.

Subependymal pseudocysts are cerebral cysts found in 5% of all neonates. When they are isolated and typical, they result from persistence of the germinal matrix, have a good prognosis and regress spontaneously within a few months. However, associated anomalies are frequent and in such cases the prognosis is poor. They can be of infectious, vascular, metabolic or chromosomal origin. Subependymal pseudocysts have rarely been described in the antenatal period. We report the prenatal diagnosis of two cases of isolated pseudocysts at 32 and 23 weeks. Both ultrasonography and magnetic resonance imaging assisted in the diagnosis and there was normal postnatal outcome in both cases.     

Gene therapy in combination with tissue engineering to treat epidermolysis bullosa

In the last 20 years epidermal stem cells have been extensively used for tissue regeneration of epidermis and other epithelial surfaces. The tremendous progress achieved has led to the development of protocols aimed at the correction of rare genetic disorders such as epidermolysis bullosa (EB), a severe, often lethal, blistering disorder of the skin. Approximately 400,000-500,000 people are affected worldwide and no definitive treatments have yet been developed. Gene therapy might represent an alternative therapeutic approach. This paper reviews the different strategies used to genetically modify keratinocytes from EB patients and addresses issues such as the use of in vivo or ex vivo approaches, how to target keratinocytes with stem cell properties in order to have long-term therapeutic gene expression, and which gene transfer agents should be used. The progress made has led the authors' group to submit a request for a Phase I/II ex vivo therapy clinical trial for patients with junctional EB.     

Stem cell therapy for intractable skin diseases

Previous studies have shown that bone marrow provides fibroblastic-like cells in the dermis and keratinocytes in the epithelia. Subsequent studies by us and other groups have demonstrated that both embryonic and postnatal transplantation of bone marrow cells in model mice of epidermolysis bullosa (EB), a heritable blistering skin disease due to genetic mutation of cutaneous basement membrane components, promote skin wound healing and correct the intrinsic basement membrane defect. We also reported that the source of the epithelial progenitors in mouse bone marrow was the nonhematopoietic, platelet-derived growth factor receptoralpha (PDGFRalpha)-positive bone marrow mesenchymal stem cell (MSC) population. In this review, recent progress as well as future perspectives of bone marrow MSC therapy for EB will be summarized.     

Progressive atrophy in the optic pathway and visual cortex of early blind Chinese adults: A voxel-based morphometry magnetic resonance imaging study

Many previous neuroimaging studies have shown that the early visual cortex of the early blind (EB) exhibits significant functional plasticity. However, only few previous studies have addressed the question whether or not such functional plasticity is accompanied by, and even related to, structural plasticity. In this study, we acquired high-resolution whole-brain anatomical magnetic resonance images form 14 Chinese EB adults, who lost sight before 6 years of age, and 16 age/gender-matched normal-sighted controls (SC), and compared pixel-by-pixel the gray matter (GM) and white matter (WM) volumes between the two groups with voxel-based morphometry. The results showed that, relative to the SC, the EB exhibits significantly reduced WM volumes in the optic tract and optic radiation and significant GM losses in the early visual cortex. The reduction of WM volume in the optic radiation of the EB was found be modulated by both the age at blindness onset and the duration of blindness. The reduction of GM volume in the early visual cortex of the EB appeared to be unaffected by the age at blindness onset. However, it was found in localized regions of the atrophic early visual cortex of the EB that the GM loss was progressive with aging and increasing duration of blindness. These results suggest that early visual deprivation induces significant structural plasticity in the optic pathway and early visual cortex of the EB, which likely occurs during both the critical period of early neurodevelopment and the course of persisted blindness later in life through activity-dependent mechanisms.     

Gene therapy in combination with tissue engineering to treat epidermolysis bullosa

In the last 20 years epidermal stem cells have been extensively used for tissue regeneration of epidermis and other epithelial surfaces. The tremendous progress achieved has led to the development of protocols aimed at the correction of rare genetic disorders such as epidermolysis bullosa (EB), a severe, often lethal, blistering disorder of the skin. Approximately 400,000 – 500,000 people are affected worldwide and no definitive treatments have yet been developed. Gene therapy might represent an alternative therapeutic approach. This paper reviews the different strategies used to genetically modify keratinocytes from EB patients and addresses issues such as the use of in vivo or ex vivo approaches, how to target keratinocytes with stem cell properties in order to have long-term therapeutic gene expression, and which gene transfer agents should be used. The progress made has led the authors’ group to submit a request for a Phase I/II ex vivo therapy clinical trial for patients with junctional EB.