Cyclosporin A impairs the secretion and activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat).

The protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients.

Mutations in lipase H cause autosomal recessive hypotrichosis simplex with woolly hair.

BACKGROUND: Mutations in lipase H (LIPH) are a rare cause of autosomal recessive hypotrichosis (HT) simplex. OBJECTIVE: In this study, we investigated the clinical and molecular basis of HT simplex with woolly hair in 3 nonrelated families. METHODS: Three families of Jewish, Arab Muslim, and Italian origin that presented with HT with woolly hair were studied. The phenotype was confirmed by clinical, microscopic, and histologic examination. Polymorphic microsatellite genotyping and direct automated DNA sequencing of the LIPH gene were used to identify the mutations in our probands. RESULTS: All patients had woolly hair since birth. At presentation, scalp hair density was reduced or normal. Sequencing of the LIPH gene revealed two homozygous mutations: a large recurrent 90-base pair duplication mutation in exon 2 in the Jewish and Arab families, and a novel deletion/insertion mutation in exon 4 in the Italian family. LIMITATIONS: Only 3 families were studied. CONCLUSION: Mutations in LIPH result in variable degrees of HT. Woolly hair is an essential component of the clinical spectrum. A hot spot in the LIPH gene may be c.280_369dup in exon 2.

Actinic damage among patients with psoriasis treated by climatotherapy at the Dead Sea.

BACKGROUND: Dead Sea climatotherapy is highly effective in the treatment of psoriasis. However, its potential side effects, especially the risk of skin cancer, are unclear. OBJECTIVE: We sought to determine the prevalence of solar damage and skin cancer among patients with psoriasis who underwent Dead Sea climatotherapy compared with control patients. METHODS: This multicenter controlled cross-sectional study was carried out at the Dead Sea Solarium Clinic and outpatient clinics of the participating centers. A total of 1198 participants (460 patients with psoriasis and 738 control patients) aged 20 to 70 years were included. A standard questionnaire including demographic parameters and sun exposure habits was administered to all participants. Patients were questioned about previous psoriatic treatments and climatotherapy at the Dead Sea. All participants underwent a structured physical examination of the skin. We compared the prevalence of solar damage for patients with psoriasis and control patients and assessed the extent of photodamage among patients with psoriasis according to exposure time at the Dead Sea in univariate and multivariate analyses. RESULTS: Elastosis ( P < .001), solar lentigines (P = .03), poikiloderma (P < .001), and facial wrinkles (P < .001) were significantly more common among patients with psoriasis compared with control patients and showed a dose response with increased Dead Sea exposure time. Self-reported previous skin cancers were more common in control patients compared with patients with psoriasis (8.2% vs 3.5%, P = .002), however, the prevalence of nonmelanoma skin cancer on examination did not differ between the two groups. No cases of malignant melanoma were detected in either group. CONCLUSIONS: Dead Sea climatotherapy is not associated with an increased risk of malignant melanoma or nonmelanoma skin cancer for patients with psoriasis in Israel. However, UV exposure at the Dead Sea may play a role in the development of solar damage.

Detection of a secreted metalloprotease within the nuclei of liver cells.

ADAMTS13 is a secreted zinc metalloprotease expressed by various cell types. Here, we investigate its cellular pathway in endogenously expressing liver cell lines and after transient transfection with ADAMTS13. Besides compartmentalizations of the cellular secretory system, we detected an appreciable level of endogenous ADAMTS13 within the nucleus. A positively charged amino acid cluster (R-Q-R-Q-R-Q-R-R) present in the ADAMTS13 propeptide may act as a nuclear localization signal (NLS). Fusing this NLS-containing region to eGFP greatly potentiated its nuclear localization. Bioinformatics analysis suggests that the ADAMTS13 CUB-2 domain has a double-stranded beta helix (DSBH) structural architecture characteristic of various protein-protein interaction modules like nucleoplasmins, class I collagenase, tumor necrosis factor ligand superfamily, supernatant protein factor (SPF) and the B1 domain of neuropilin-2. Based on this contextual evidence and that largely conserved polar residues could be mapped on to a template CUB domain homolog, we hypothesize that a region in the ADAMTS13 CUB-2 domain with conserved polar residues might be involved in protein-protein interaction within the nucleus.

A splice variant of ADAMTS13 is expressed in human hepatic stellate cells and cancerous tissues.

Although ADAMTS13, the von Willebrand factor (VWF)-cleaving protease, is expressed in a range of tissues, the physiological significance of tissue-specific ADAMTS13 alternative splicing isoforms have yet to be clarified. Screening a panel of human tissues and cell lines revealed a spliced ADAMTS13 transcript in hepatic stellate cells and a hepatoma cell line that retains the 25th intron. A nonsense codon within the intron truncates the protease, which gains 64 novel amino acids in lieu of both CUB domains. This isoform, while retaining VWF-cleaving capability, accumulates intracellularly and its biological inaccessibility may prevent its participation in regulating haemostasis and other physiologic functions.

The inhibitor of apoptosis protein Livin (ML-IAP) plays a dual role in tumorigenicity.

The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We and others previously described the IAP Livin (ML-IAP). We found that Livin is unique among the IAP members as, on a strong apoptotic stimulus, it is specifically cleaved by caspases to produce a truncated protein with paradoxical proapoptotic activity (tLivin). We also showed that Livin encodes two splicing variants, termed Livin alpha and beta, with diverse antiapoptotic effects in vitro. In this study, we compared the Livin isoforms in vivo. An animal model was established and the effects of Livin alpha and beta on the initiation and development of tumors were compared. In the animal model, Livin alpha promotes tumor initiation in comparison with control. Interestingly, the growth of tumors originating from cells expressing Livin beta was inhibited. In these tumors, Livin beta was cleaved and produced a high level of the proapoptotic tLivin beta that repressed tumor development. When we eliminated the proapoptotic effect of Livin beta by point mutations, the resulting antiapoptotic Livin beta mutants contributed to tumor progression. In terms of mechanism, we show that Livin beta tumors develop only in mice lacking natural killer (NK) cell activity. Thus, from the animal model, we can conclude that Livin plays a major role in tumorigenicity and that NK cells induce cleavage of Livin to its proapoptotic truncated protein that in turn inhibits tumor growth. Therefore, Livin and tLivin may serve as potential targets for cancer therapy.

Increased prevalence of onychomycosis among psoriatic patients in Israel.

Published data on the prevalence of onychomycosis in psoriasis patients compared with healthy controls are controversial, We therefore conducted a prospective study of toenail onychomycosis, among 113 psoriatic and 106 healthy non-psoriatic subjects, selected from the normal population in the Jerusalem area in the period 2003-05. The results revealed a prevalence of 47.6% toenail onychomycosis among psoriatic patients, compared with 28.4% in normal controls (p=0.0054). Both gender and age affected the prevalence of onychomycosis in both psoriatic and healthy controls, with a higher prevalence in male and elderly subjects. The type and duration of psoriasis were also found to have an impact on the prevalence of onychomycosis. However, the body area involved did not affect the prevalence of onychomycosis in psoriatic patients. Approximately the same percentages of dermatophytes and yeasts were found in psoriatic patients as in healthy controls. However, a higher percentage of moulds was found in psoriatic patients.

Prevalence of Candida on the tongue and intertriginous areas of psoriatic and atopic dermatitis patients.

Data in the literature regarding the prevalence of Candida in psoriatic and atopic dermatitis patients are controversial. We conducted a prospective study to determine the prevalence of Candida on the tongue, axillae and groin of psoriatic patients when compared with atopic dermatitis patients and normal controls. During the period 2003-2005, data were collected from 100 psoriatic patients, 100 patients with atopic dermatitis and 100 normal controls. Fungal test specimens for Candida were collected from the axillae, groin and tongue of each patient. There was no increase in the prevalence of Candida in intertriginous area of either psoriatic or atopic dermatitis patients. However, the prevalence of Candida on the tongue was significantly higher in psoriatic patients (32%) compared with atopic dermatitis (18%) (P = 0.024) and higher, although not significantly, than in normal controls (21%) (P = 0.08). Our study did not reveal higher prevalence of Candida in the axillae and groin of either psoriatic or atopic dermatitis patients. There was a higher prevalence of Candida on the tongue of psoriatic patients. The Candida of the tongue was asymptomatic and did not correlate with age, gender, type of psoriasis or severity of the disease, therefore we conclude that this is clinically irrelevant.

Exploring the mango-poison ivy connection: the riddle of discriminative plant dermatitis.

A relationship between sensitivity to poison oak or poison ivy and mango dermatitis has been suggested by previous publications. The observation that acute allergic contact dermatitis can arise on first exposure to mango in patients who have been sensitized beforehand by contact with other urushiol-containing plants has been documented previously. We report 17 American patients employed in mango picking at a summer camp in Israel, who developed a rash of varying severity. All patients were either in contact with poison ivy/oak in the past or lived in areas where these plants are endemic. None recalled previous contact with mango. In contrast, none of their Israeli companions who had never been exposed to poison ivy/oak developed mango dermatitis. These observations suggest that individuals with known history of poison ivy/oak allergy, or those residing in area where these plants are common, may develop allergic contact dermatitis from mango on first exposure. We hypothesize that previous oral exposure to urushiol in the local Israeli population might establish immune tolerance to these plants.

Andogsky syndrome variant: atopic dermatitis associated with bilateral cataracts and retinal degeneration with left retinal detachment.

A 15-year-old girl had a new variation of Andogsky syndrome (unilateral cataract and atopic dermatitis) in which atopic dermatitis was associated with primary bilateral cataracts and retinal degeneration with primary left retinal detachment before cataract surgery. She had no history of systemic steroid treatment.

Herpes simplex virus infection in a hyper-IgE patient: appearance of unusual mass lesions.

A 7-year-old girl presented with large soft masses rising from the nostril and from behind the ear. She had previously been diagnosed as suffering from hyper-IgE syndrome. The presence of herpes simplex virus infection within these lesions was confirmed by biopsy and immunohistochemical studies. The mass lesions did not respond to antibacterial therapy with cefazolin, but improved promptly under antiviral therapy with acyclovir. Immunological studies revealed a mild decrease in the CD4 cell population. Based on our results and on the relevant literature we propose an immunological mechanism for this unique manifestation of herpes simplex virus infection in hyper-IgE syndrome.

A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: a syndrome of dysregulated matrix remodeling?

Nephrogenic fibrosing dermopathy (NFD) is a disorder characterized by dramatic thickening and hardening of skin in the extremities and trunk, which occurs in individuals on dialysis for renal disease. The pathophysiology is unknown. Increased transforming growth factor-beta (TGF-beta) and collagen deposition have been reported in a small group of patients studied by Jimenez et al.1 We report two patients with NFD and osteoclast-like giant cells in the fibrotic dermis; one patient also had dystrophic cutaneous calcification. These findings have been seen in a small percentage of NFD patients (estimated 2-5%) and may represent a variant of the disease. The hypothesis of altered matrix dysregulation due to altered TGF-beta, metalloproteinases, and activation of osteoclasts as an explanation for this variant is proposed.