Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis

Abstract:  Understanding the acantholytic pathways leading to blistering in pemphigus vulgaris (PV) is a key to development of novel treatments. A novel paradigm of keratinocyte damage in PV, termed apoptolysis, links the suprabasal acantholytic and cell death pathways to basal cell shrinkage rendering a 'tombstone' appearance to PV lesions. In contrast to apoptolysis, the classic keratinocyte apoptosis mediating toxic epidermal necrolysis causes death and subsequent sloughing of the entire epidermis. Apoptolysis includes five consecutive steps. (1) Binding of autoantibodies to PV antigens. (2) Activation of EGF receptor, Src, mTOR, p38 MAPK and other signalling elements downstream of ligated antigens, elevation of intracellular calcium and launching of the cell death cascades. (3) Basal cell shrinkage due to: (i) collapse and retraction of the tonofilaments cleaved by executioner caspases; and (ii) dissociation of interdesmosomal adhesion complexes caused by phosphorylation of adhesion molecules. (4) Massive cleavage of cellular proteins by activated cell death enzymes leading to cell collapse, and tearing off desmosomes from the cell membrane stimulating secondary autoantibody production. (5) Rounding up and death of acantholytic cells. Thus, the structural damage (acantholysis) and death (apoptosis) of keratinocytes are mediated by the same cell death enzymes. Appreciation of the unifying concept of apoptolysis have several important implications: (i) linking together a number of seemingly unrelated events surrounding acantholysis; (ii) opening new avenues of investigation into the pathomechanism of pemphigus; and (iii) creating new approaches to the treatment of pemphigus based on blocking the signalling pathways and enzymatic processes that lead to blistering.     

Detection of Undiagnosed Coeliac Disease with Atypical Features Using Antireticulin and Antigliadin Antibodies

Eighteen patients with a variety of non-gastrointestinal symptomswere incidentally found to have circulating antireticulin antibodyand on subsequent testing were also positive for antigliadinantibody. They prospectively underwent jejunal biopsy to determinewhether or not they had coeliac disease. Their age range was21–79 years (mean 42 years). Enteropathy was present in13 (72 per cent) and was always associated with circulatingIgA antigliadin antibody. Enteropathy was not present in thefive cases who had only IgG antibody. Clinical improvement occurredin eight of 11 patients who complied with a gluten-free dietand was paralleled by an improvement in the mucosal histologyin seven of eight who were re-biopsied. The most remarkablecases were two patients who presented with severe debility andno apparent haematological or biochemical abnormalities, andwho subsequently made a dramatic recovery on a gluten-free diet.It is concluded that antireticulin antibody detected by routineautoantibody screening and confirmed to have IgA antigliadinantibody specificity is a useful indicator of an otherwise undiagnosedenteropathy. This serves to emphasize that the condition cansometimes be associated with atypical features and significantmorbidity.     

Verletzungsmuster und -ursachen in modernen Kriegen

Epidemiological analyses of injury patterns and mechanisms help to identify the expertise military surgeons need in a combat setting and accordingly help to adjust infrastructure and training requirements. Therefore, a MEDLINE search (1949–2009), World Wide Web search (keywords “combat, casualties, war, military, wounded and neurosurgery”) and an analysis of deaths among allied war casualties in Afghanistan and Iraq were performed. Up to 10th December 2009 there had been 4,688 allied military deaths in Iraq and 1,538 in Afghanistan. Of these 22% died in non-hostile action, 33% in direct combat situations and the majority of 45% in indirect combat actions. The leading causes of injury were explosive devices (70%) and gunshot wounds. Chest or abdominal injuries (40%) and traumatic brain injuries (35%) were the main causes of death for soldiers killed in action. The case fatality rate in Iraq is approximately half that of the Vietnam War, whereas the killed-in-action rate in Afghanistan (18.7%) is similar to the Vietnam War (20%); however, the amputation rate is twice as high in modern conflicts. Approximately 8–15% of the fatal injuries seem to be potentially survivable. Military surgeons must have an excellent expertise in a wide variety of surgical specialties. Life saving emergency care, especially in the fields of thoracic, visceral and vascular surgery as well as practical skills in the fields of neurosurgery and oral and maxillofacial surgery are required. Additionally, it is of vital importance to ensure the availability of sufficient tactical and strategic medical evacuation capabilities for the wounded.     

Persistence of CCR5 usage among primary human immunodeficiency virus isolates of individuals receiving intermittent interleukin‐2

Objective

To investigate the impact of intermittent interleukin‐2 (IL‐2) plus combination antiretroviral therapy (cART) on HIV‐1 entry co‐receptor use.

Methods

Primary HIV‐1 isolates were obtained from 54 HIV‐1‐positive individuals at baseline and after 12 months using co‐cultivation of peripheral blood mononuclear cells (PBMC) with activated PBMC of HIV‐negative healthy donors. HIV‐1 co‐receptor use was determined on U87‐CD4 cells.

Results

Fourteen out of the 21 (67%) IL‐2‐treated individuals harbouring a primary CCR5‐dependent (R5) HIV‐1 isolate at baseline confirmed an R5 virus isolation after 12 months in contrast to 3 out of 7 (43%) of those receiving cART only. After 12 months, only 1 R5X4 HIV‐1 isolate was obtained from 21 cART+IL‐2‐treated individuals infected with an R5 virus at entry (5%) vs. 2/7 (29%) patients receiving cART alone, as confirmed by a 5‐year follow‐up on some individuals.

Conclusions

Intermittent IL‐2 administration plus cART may prevent evolution towards CXCR4 usage in individuals infected with R5 HIV‐1.

     

实验动物皮肤病原真菌检测方法的改良

目的对实验动物皮肤病原真菌2种培养方法进行了比较。方法将采集到的3只皮肤真菌感染病兔样品经由沙氏平皿法和沙氏试管斜面培养法分别进行培养。结果在3只真菌感染病兔中应用试管斜面法我们只检测到1例皮肤病原真菌阳性,而采用沙氏平皿法3例阳性全部检出。结论结合临床检测经验,我们认为本研究的沙氏平皿法优于沙氏试管斜面法,在实验动物皮肤病原真菌常规检测中具有推广应用价值。     

栀蒡热毒平有效组分中栀子苷、牛蒡子苷和黄芩苷在大鼠体内血药浓度测定

目的 建立大鼠血浆中栀蒡热毒平方有效组分中栀子苷、牛蒡子苷和黄芩苷的HPLC血药浓度测定方法.方法 血浆样品采用甲醇-乙腈(1∶ 1)沉淀蛋白,HPLC测定血药浓度.色谱柱为Diamonsil C18柱(4.6 mm×150 mm, 5 μm),流动相乙腈-0.2%磷酸水梯度洗脱,流速1.0 mL/min,检测波长238 nm和278 nm.结果 各成分的最低检测浓度(S/N＞3)在0.23~0.32 mg/L,平均回收率均在85%以上,日内、日间精密度及稳定性的RSD均小于10%.结论 该方法简便、准确,可作为栀蒡热毒平方血药浓度定量分析方法.