Development and validation of a vitiligo-specific quality-of-life instrument (VitiQoL).

BACKGROUND: Vitiligo significantly affects a person's health-related quality of life (HRQL). Although a small number of generic, and disease-specific, dermatologic HRQL measures exist, currently no vitiligo-specific instrument is available to capture disease-targeted concerns and issues. OBJECTIVE: We sought to develop and validate a vitiligo-specific self-report instrument for HRQL. METHODS: A pool of vitiligo-specific items was created based on in-depth interviews with patients with vitiligo (n = 16) and their responses to items in several previously validated HRQL measures. These items comprising our new instrument, VitiQoL, along with Skindex-16 and Dermatology Life Quality Index were administered to patients with vitiligo (n = 90) at two academic centers. This new instrument was validated using psychometric analysis. RESULTS: The VitiQoL items showed high internal consistency (Cronbach alpha = 0.935). Exploratory factor analysis demonstrated 3 factors: participation limitation, stigma, and behavior. Concurrent validity was evidenced by large correlations between self-reported severity and VitiQoL scores (r = 0.51). Known groups validity was demonstrated for the VitiQoL behavior subscale between individuals with exposed and unexposed patches (P = .01). Convergent validity was shown by strong correlations between VitiQoL and outside dermatology scales measuring similar constructs (Skindex-16, r = 0.82; Dermatology Life Quality Index, r = 0.83). LIMITATIONS: Potential selection bias was a limitation as most patients were recruited from academic centers. Reliability of the instrument was tested only with internal consistency and not reproducibility. Responsiveness of the instrument was not tested because of the prolonged time course necessary to observe clinically significant change in vitiligo. CONCLUSION: VitiQoL is a reliable and valid HRQL instrument.

Pemphigoid gestationis.

Pemphigoid gestationis is a rare autoimmune blistering disease of pregnancy. It is characterized by pruritic, urticarial plaques with the development of tense vesicles and bullae within the lesions. Pemphigoid gestationis has been associated with premature delivery, small-for-gestational-age infants. Recurrences with subsequent pregnancies are often more severe. Oral glucocorticoids are the mainstay of therapy. Differentiation of pemphigoid gestationis from pruritic urticarial papules and plaques of pregnancy is essential because management and outcomes differ. In instances in which clinical diagnosis is difficult, direct immunofluorescence tests, immunoblots, or ELISA studies of anti-basement-membrane zone antibodies are useful in establishing the diagnosis.

Generalized eruptive keratoacanthomas of Grzybowski.

A 48-year-old man presented with a two-year history of a generalized, pruritic eruption that was associated with numerous, dome-shaped papules and nodulocystic lesions. Biopsy specimens have shown keratoacanthomas and a lichenoid dermatitis. Evaluation for malignant conditions has been negative. Owing to the constellation of findings, a diagnosis of generalized eruptive keratoacanthomas of Grzybowski associated with lichenoid dermatitis and acneiform lesions is favored. The patient is currently on a trial of acitretin.

Hypohidrotic ectodermal dysplasia.

We report three children with hypohidrotic ectodermal dysplasia (HED), which includes two sisters with unaffected parents (and therefore likely autosomal recessive inheritance of HED) and an unrelated boy. Each patient presented with hypohidrosis, sparse hair, oligodontia with conical teeth, periorbital hyperpigmentation, eczematous dermatitis, and facial features that include frontal bossing, a saddle nose, and prominent lips. HED is caused by defects in the ectodysplasin signal transduction pathway. Mutations in the gene encoding the ligand ectodysplasin A (EDA) underlie classic, X-linked recessive HED, whereas mutations in the genes encoding the EDA receptor and (less frequently) the adaptor protein that associates with the EDA receptor's death domain result in autosomal dominant and autosomal recessive forms of HED.

CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism.

There is increasing evidence that neuron death in neurodegenerative diseases, such as Parkinson's disease, is due to the activation of programmed cell death. However, the upstream mediators of cell death remain largely unknown. One approach to the identification of upstream mediators is to perform gene expression analysis in disease models. Such analyses, performed in tissue culture models induced by neurotoxins, have identified up-regulation of CHOP/GADD153, a transcription factor implicated in apoptosis due to endoplasmic reticulum stress or oxidative injury. To evaluate the disease-related significance of these findings, we have examined the expression of CHOP/GADD153 in neurotoxin models of parkinsonism in living animals. Nuclear expression of CHOP protein is observed in developmental and adult models of dopamine neuron death induced by intrastriatal injection of 6-hydroxydopamine (6OHDA) and in models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). CHOP is a mediator of neuron death in the adult 60HDA model because a null mutation results in a reduction in apoptosis. In the chronic MPTP model, however, while CHOP is robustly expressed, the null mutation does not protect from the loss of neurons. We conclude that the role of CHOP depends on the nature of the toxic stimulus. For 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.

Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2.

Numerous stressful conditions activate kinases that phosphorylate the alpha subunit of translation initiation factor 2 (eIF2alpha), thus attenuating mRNA translation and activating a gene expression program known as the integrated stress response. It has been noted that conditions associated with eIF2alpha phosphorylation, notably accumulation of unfolded proteins in the endoplasmic reticulum (ER), or ER stress, are also associated with activation of nuclear factor kappa B (NF-kappaB) and that eIF2alpha phosphorylation is required for NF-kappaB activation by ER stress. We have used a pharmacologically activable version of pancreatic ER kinase (PERK, an ER stress-responsive eIF2alpha kinase) to uncouple eIF2alpha phosphorylation from stress and found that phosphorylation of eIF2alpha is both necessary and sufficient to activate both NF-kappaB DNA binding and an NF-kappaB reporter gene. eIF2alpha phosphorylation-dependent NF-kappaB activation correlated with decreased levels of the inhibitor IkappaBalpha protein. Unlike canonical signaling pathways that promote IkappaBalpha phosphorylation and degradation, eIF2alpha phosphorylation did not increase phosphorylated IkappaBalpha levels or affect the stability of the protein. Pulse-chase labeling experiments indicate instead that repression of IkappaBalpha translation plays an important role in NF-kappaB activation in cells experiencing high levels of eIF2alpha phosphorylation. These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-kappaB during ER stress.

Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response.

Stress-induced eukaryotic translation initiation factor 2 (eIF2) alpha phosphorylation paradoxically increases translation of the metazoan activating transcription factor 4 (ATF4), activating the integrated stress response (ISR), a pro-survival gene expression program. Previous studies implicated the 5' end of the ATF4 mRNA, with its two conserved upstream ORFs (uORFs), in this translational regulation. Here, we report on mutation analysis of the ATF4 mRNA which revealed that scanning ribosomes initiate translation efficiently at both uORFs and ribosomes that had translated uORF1 efficiently reinitiate translation at downstream AUGs. In unstressed cells, low levels of eIF2alpha phosphorylation favor early capacitation of such reinitiating ribosomes directing them to the inhibitory uORF2, which precludes subsequent translation of ATF4 and represses the ISR. In stressed cells high levels of eIF2alpha phosphorylation delays ribosome capacitation and favors reinitiation at ATF4 over the inhibitory uORF2. These features are common to regulated translation of GCN4 in yeast. The metazoan ISR thus resembles the yeast general control response both in its target genes and its mechanistic details.

Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2.

Transient phosphorylation of the alpha-subunit of translation initiation factor 2 (eIF2alpha) represses translation and activates select gene expression under diverse stressful conditions. Defects in the eIF2alpha phosphorylation-dependent integrated stress response impair resistance to accumulation of malfolded proteins in the endoplasmic reticulum (ER stress), to oxidative stress and to nutrient deprivations. To study the hypothesized protective role of eIF2alpha phosphorylation in isolation of parallel stress signaling pathways, we fused the kinase domain of pancreatic endoplasmic reticulum kinase (PERK), an ER stress-inducible eIF2alpha kinase that is normally activated by dimerization, to a protein module that binds a small dimerizer molecule. The activity of this artificial eIF2alpha kinase, Fv2E-PERK, is subordinate to the dimerizer and is uncoupled from upstream stress signaling. Fv2E-PERK activation enhanced the expression of numerous stress-induced genes and protected cells from the lethal effects of oxidants, peroxynitrite donors and ER stress. Our findings indicate that eIF2alpha phosphorylation can initiate signaling in a cytoprotective gene expression pathway independently of other parallel stress-induced signals and that activation of this pathway can single-handedly promote a stress-resistant preconditioned state.

An integrated stress response regulates amino acid metabolism and resistance to oxidative stress.

Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.