Eponyms and clinical entities from the land of Israel.

Seven eponyms have been pioneered by dermatologists in Israel: Brenner's sign, Chanarin-Dorfman syndrome, granulated sweetener packet sign, isopathic phenomenon of Sagher, lanolin paradox, Nakar-Ingber disease, and Wolf's isotopic response. In addition, there are three id reactions described by Israeli dermatologists: leishmanid, pediculid, and scabid. There is also the acronym PEMPHIGUS, which stands for the causative reasons for pemphigus. We celebrate these eponyms and clinical entities, which reflect the impressive progress made by dermatologists in Israel during the past century who have helped to build an academic, vibrant, and dynamic specialty in the Holy Land.

Plant mitochondrial RNA editing factors can perform targeted C-to-U editing of nuclear transcripts in human cells.

RNA editing processes are strikingly different in animals and plants. Up to thousands of specific cytidines are converted into uridines in plant chloroplasts and mitochondria whereas up to millions of adenosines are converted into inosines in animal nucleo-cytosolic RNAs. It is unknown whether these two different RNA editing machineries are mutually incompatible. RNA-binding pentatricopeptide repeat (PPR) proteins are the key factors of plant organelle cytidine-to-uridine RNA editing. The complete absence of PPR mediated editing of cytosolic RNAs might be due to a yet unknown barrier that prevents its activity in the cytosol. Here, we transferred two plant mitochondrial PPR-type editing factors into human cell lines to explore whether they could operate in the nucleo-cytosolic environment. PPR56 and PPR65 not only faithfully edited their native, co-transcribed targets but also different sets of off-targets in the human background transcriptome. More than 900 of such off-targets with editing efficiencies up to 91%, largely explained by known PPR-RNA binding properties, were identified for PPR56. Engineering two crucial amino acid positions in its PPR array led to predictable shifts in target recognition. We conclude that plant PPR editing factors can operate in the entirely different genetic environment of the human nucleo-cytosol and can be intentionally re-engineered towards new targets.

Effect of Solar Radiation on Skin Microbiome: Study of Two Populations.

Here, we examined the skin microbiome of two groups of healthy volunteers living on the Mediterranean coast with different exposures to sun radiation. One group, exposed to the sun in the summer, was compared with a group covered with clothing throughout the year. The seasonal effects on the skin microbiome of three body sites were determined before and after summer. Surprisingly, at the phyla level, there were no significant differences in microbiome diversity between the groups. Furthermore, within each group, there were no significant seasonal differences in high-abundance species at any of the sampling sites. These results suggest that the skin microbiome, developed over years, remains stable even after several months of exposure to summer weather, direct sunlight and humidity. However, in the group exposed to the sun during the summer months, there were significant differences in low-abundance species in sun-exposed areas of the skin (the inner and outer arm). These subtle changes in low-abundance species are interesting, and their effect on skin physiology should be studied further.

The dual-targeted RNA editing factor AEF1 is universally conserved among angiosperms and reveals only minor adaptations upon loss of its chloroplast or its mitochondrial target.

KEY MESSAGE: Upon loss of either its chloroplast or mitochondrial target, a uniquely dual-targeted factor for C-to-U RNA editing in angiosperms reveals low evidence for improved molecular adaptation to its remaining target. RNA-binding pentatricopeptide repeat (PPR) proteins specifically recognize target sites for C-to-U RNA editing in the transcriptomes of plant chloroplasts and mitochondria. Among more than 80 PPR-type editing factors that have meantime been characterized, AEF1 (or MPR25) is a special case given its dual targeting to both organelles and addressing an essential mitochondrial (nad5eU1580SL) and an essential chloroplast (atpFeU92SL) RNA editing site in parallel in Arabidopsis. Here, we explored the angiosperm-wide conservation of AEF1 and its two organelle targets. Despite numerous independent losses of the chloroplast editing site by C-to-T conversion and at least four such conversions at the mitochondrial target site in other taxa, AEF1 remains consistently conserved in more than 120 sampled angiosperm genomes. Not a single case of simultaneous loss of the chloroplast and mitochondrial editing target or of AEF1 disintegration or loss could be identified, contrasting previous findings for editing factors targeted to only one organelle. Like in most RNA editing factors, the PPR array of AEF1 reveals potential for conceptually "improved fits" to its targets according to the current PPR-RNA binding code. Surprisingly, we observe only minor evidence for adaptation to the mitochondrial target also after deep losses of the chloroplast target among Asterales, Caryophyllales and Poales or, vice versa, for the remaining chloroplast target after a deep loss of the mitochondrial target among Malvales. The evolutionary observations support the notion that PPR-RNA mismatches may be essential for proper function of editing factors.

Multifarious Evolutionary Pathways of a Nuclear RNA Editing Factor: Disjunctions in Coevolution of DOT4 and Its Chloroplast Target rpoC1eU488SL.

Nuclear-encoded pentatricopeptide repeat (PPR) proteins are site-specific factors for C-to-U RNA editing in plant organelles coevolving with their targets. Losing an editing target by C-to-T conversion allows for eventual loss of its editing factor, as recently confirmed for editing factors CLB19, CRR28, and RARE1 targeting ancient chloroplast editing sites in flowering plants. Here, we report on alternative evolutionary pathways for DOT4 addressing rpoC1eU488SL, a chloroplast editing site in the RNA polymerase ß' subunit mRNA. Upon loss of rpoC1eU488SL by C-to-T conversion, DOT4 got lost multiple times independently in angiosperm evolution with intermediate states of DOT4 orthologs in various stages of degeneration. Surprisingly, we now also observe degeneration and loss of DOT4 despite retention of a C in the editing position (in Carica, Coffea, Vicia, and Spirodela). We find that the cytidine remains unedited, proving that DOT4 was not replaced by another editing factor. Yet another pathway of DOT4 evolution is observed among the Poaceae. Although the rpoC1eU488SL edit has been lost through C-to-T conversion, DOT4 orthologs not only remain conserved but also have their array of PPRs extended by six additional repeats. Here, the loss of the ancient target has likely allowed DOT4 to adapt for a new function. We suggest rps3 antisense transcripts as previously demonstrated in barley (Hordeum vulgare) arising from promotor sequences newly emerging in the rpl16 intron of Poaceae as a new candidate target for the extended PPR stretch of DOT4. Altogether, DOT4 and its target show more flexible pathways for evolution than the previously explored editing factors CLB19, CRR28, and RARE1. Certain plant clades (e.g., Amaranthus, Vaccinium, Carica, the Poaceae, Fabales, and Caryophyllales) show pronounced dynamics in the evolution of editing sites and corresponding factors.

Generating Attention, Inhibition, and Memory: A Pilot Randomized Trial for Preschoolers With Executive Functioning Deficits.

This goal of this study was to assess the initial feasibility and efficacy of a play-based intervention targeting executive functions (EF) and parent-child relationships in preschoolers compared with an active control group. Preschoolers with EF deficits (M age = 3.7 ± 0.47, predominantly White boys) and their parents were randomized to intervention (n = 36) or active control (n = 32) conditions. Child performance on EF tasks, parent and masked teacher ratings of EF and behavior, and masked clinician ratings of severity were collected at baseline and at 3 and 6 months postbaseline. Partial eta-squared effect sizes at .02 or higher comparing performance across the two groups was considered evidence of meaningful, albeit small, intervention effects. Intervention effects were observed for parent ratings of inattention, hyperactivity/impulsivity, and number/severity of problems experienced in various home situations, teacher ratings of severity of problems in various school situations, parent and teacher ratings of overall impairment, and clinician ratings of impairment. Intervention effects for functional improvements were maintained at the 6-month follow-up. No effect of the intervention was observed on the objective EF measures, although parent ratings of emotional control were improved for children in the intervention group. An intervention utilizing play-based activities targeting EF, when administered in a structured way by parents, is a promising approach for improving behavior in preschoolers with self-regulation deficits. More work is needed to investigate potential impact on EF and to disentangle mechanisms of action. It may be that the intervention's focus on the structure and quality of parent-child interactions is a mediator of outcomes, rather than improved EFs.

Are sluggish cognitive tempo symptoms associated with executive functioning in preschoolers?

The aim of this study is to investigate whether sluggish cognitive tempo (SCT) symptoms are associated with neurocognitive task performance and ratings of real-world executive functioning (EF) in preschoolers at risk for attention-deficit/hyperactivity disorder (ADHD). The associations between parent- and teacher-rated SCT symptoms and neuropsychological task performance and ratings of EF in 61 4-year-old preschool children (51 boys, 10 girls) with self-regulation difficulties were examined, with regression analyses controlling for the effects of ADHD inattention symptoms. In the study sample, higher teacher-rated SCT symptoms are significantly associated with poorer performance on tasks of visual-perceptual abilities, auditory and visual attention, sustained and selective attention, inhibitory control, pre-numerical/numerical concepts, and slower processing speed, but SCT symptoms are not significantly associated with working memory, attention shifting or cognitive flexibility when controlling for ADHD inattention. Higher parent-rated SCT symptoms are significantly associated with visual-perceptual abilities. ADHD inattention symptoms are more strongly associated than SCT with daily life EF ratings; neither parent- nor teacher-rated SCT symptoms are significantly associated with daily life ratings of inhibition, working memory, or planning/organization after controlling for ADHD inattention. This study suggests that SCT symptoms contribute to EF deficits at least on neurocognitive tasks assessing visual-perceptual/spatial abilities, attention to detail and processing speed, as observed in this sample of young children at risk for ADHD, and may be an important intervention target.

Photo-damage protective effect of two facial products, containing a unique complex of Dead Sea minerals and Himalayan actives.

BACKGROUND: Skin appearance is badly affected when exposed to solar UV rays, which encourage physiological and structural cutaneous alterations that eventually lead to skin photo-damage. AIMS: To test the capability of two facial preparations, extreme day cream (EXD) and extreme night treatment (EXN), containing a unique complex of Dead Sea water and three Himalayan extracts, to antagonize biological effects induced by photo-damage. METHODS: Pieces of organ cultures of human skin were used as a model to assess the biological effects of UVB irradiation and the protective effect of topical application of two Extreme preparations. Skin pieces were analyzed for mitochondrial activity by MTT assay, for apoptosis by caspase 3 assay, and for cytokine secretion by solid phase ELISA. Human subjects were tested to evaluate the effect of Extreme preparations on skin wrinkle depth using PRIMOS and skin hydration by a corneometer. RESULTS: UVB irradiation induced cell apoptosis in the epidermis of skin organ cultures and increased their pro-inflammatory cytokine, tumor necrosis α (TNFα) secretion. Topical applications of both preparations significantly attenuated all these effects. Furthermore, in human subjects, a reduction in wrinkle depth and an elevation in the intense skin moisture were observed. CONCLUSIONS: The observations clearly show that EXD and EXN preparations have protective anti-apoptotic and anti-inflammatory properties that can attenuate biological effects of skin photo-damage. Topical application of the preparations improves skin appearance by reducing its wrinkles depth and increasing its moisturizing impact.

In vitro release of interferon-gamma from peripheral blood lymphocytes in cutaneous adverse drug reactions.

BACKGROUND: Cutaneous drug reactions are common but diagnostically challenging due to phenotypic heterogeneity and simultaneous exposure to multiple drugs. These limitations prompted the development of diagnostic tests. AIMS: To evaluate the performance of an in vitro assay measuring interferon-gamma release from patients' lymphocytes in the presence of causative drugs for the diagnosis of drug reactions. METHODS: Mononuclear cells derived from patients were incubated with and without suspected drugs, and increment of interferon-gamma levels was measured by ELISA. We performed a telephonic survey to evaluate the effect of stopping the drugs incriminated by the assay on cutaneous manifestations. RESULTS: We assessed 272 patients who used 1035 medications. When assessed against the questionnaire data collected at least 6 months after stopping the causative drug, sensitivity was found to be 83.61% and specificity 92.67%. Likelihood ratio for a positive test is 11.40 and for a negative test 0.18. Positive predictive value is 75.37% and negative predictive value is 95.47%. The test was found to perform significantly better in females and in older patients. CONCLUSIONS: Interferon-gamma release test is a useful adjunct tool in the diagnosis of cutaneous drug reactions.

Drug-induced pemphigus.

Pemphigus is an autoimmune bullous disease that may be influenced by genetic and exogenous factors. Drugs are a leading cause of pemphigus. There is a need for a thorough history taking so as to find the culprit medication. The diagnosis of drug-induced pemphigus is challenging. Patients have often been exposed to multiple drugs, and some drugs may have a prolonged latency period between exposure and onset of the disease. The in vitro interferon-gamma (IFN-gamma) release from lymphocytes test has been shown to be of diagnostic value in drug-induced skin reactions. Cessation of the offending drug may alleviate the clinical manifestations and reduce the need for medical treatment.

Differences in cytokine levels in melanoma patients with and without redness (Brenner sign).

BACKGROUND: In view of several studies highlighting an observation of an erythematous eruption in the vicinity of or distant from the lesion in melanoma patients (The Brenner sign), this study sought to assess whether this phenomenon might be related to the blood level of cytokines IL-6 and IL-8. PATIENTS AND METHODS: Sera specimens obtained from 27 patients with melanoma, of which 15 had erythematous eruptions and 12 did not, were studied by immunohistochemistry for the expression of IL-6 and IL-8. RESULTS: IL-6 was detected in all melanoma patients in both groups. The mean level of IL-6 in the redness group (2.41 pg/L) was significantly higher than in the group without redness (1.25 pg/L). IL-8 was detected in all 27 melanoma patients in the two groups. The serum level was less than 5 pg/L in only 1 patient (6.7%) in the redness group, and in 6 patients (50%) in the group without redness, a statistically significant difference. CONCLUSION: The Brenner sign appears to reflect a more advanced disease and herald a poor prognosis according to its correlation with the IL-8 and IL-6 blood level. However, in view of the biphasic effect of IL-8 level on tumor progression, and IL-6's ability to inhibit early stage melanoma, redness in melanoma patients could be a sign of a better prognosis of the melanoma.

Eczema craquelé with purpura: a sign of internal malignancy or malabsorption syndrome?

We describe a patient with eczema craquelé associated with adenocarcinoma of the pancreas. Following a Whipple operation, zinc malabsorption was ruled out as the cause based on the distribution of the dermatitis, alkaline phosphatase levels within reference range, and response to pancreatic enzyme replacement therapy. Because the patient's skin changes appeared following removal of the malignancy and resolved shortly after the second course of pancreatic enzyme replacement therapy, fat malabsorption probably was responsible for the skin changes rather than a direct paraneoplastic expression of the cancer. The occurrence of purpura with eczema craquele has not been previously described in the literature. These findings raise the possibility that generalized eczema craquele is a diagnostic clue to a malignancy and argue for adding it to the list of cutaneous paraneoplastic syndromes.

Interferon-gamma (INF-gamma) release test can detect cutaneous adverse effects to statins.

BACKGROUND: An increasing number of cutaneous adverse effects are being reported as use of statins becomes more widespread. A study was undertaken to establish the relationship between statin and a cutaneous reaction by the in vitro interferon-gamma (INF-gamma) release test. METHODS: The lymphocytes of 20 patients with suspected drug-induced skin reaction were incubated with and without the drug. The level of INF-gamma from the supernatant was measured by enzyme-linked immunosorbent assay (ELISA), and the increase calculated. RESULTS: Response was positive in 27 (21.43%) of the 126 drugs. Statin was the only drug with a positive response in 80% of those cases. Nine of 20 patients (45.0%) had complete resolution after discontinuation of the drug; 6 (30.0%) who replaced one drug by another statin had partial or no resolution; and 5 (20.0%) had no resolution despite cessation of statins of all kinds. CONCLUSION: A positive INF-gamma release test was found in patients who developed skin reactions while taking statins; the test's reliability was strengthened by prompt improvement following elimination of the suspected drug in the majority of patients.

In vitro interferon-gamma release test in patients with drug-induced pemphigus.

BACKGROUND: Drug-specific CD8+ TH1 lymphocytes have been found in the peripheral blood and involved skin of patients with drug-induced bullous exanthems. OBJECTIVES: To determine whether the interferon-gamma release test can identify culprit drugs in pemphigus patients. METHODS: Clinical and laboratory workup for pemphigus was performed in 14 pemphigus vulgaris patients who had been exposed to drugs, and the IFN-gamma release test was conducted on their lymphocytes from heparinized venous blood cultured with medium, phytohemagglutinin and one of 32 drugs, or medium and phytohemagglutinin alone. RESULTS: Ten of the patients and 13 of the 32 drugs exhibited a positive response to the test. Eight of the 10 patients with positive IFN-gamma test results had a less severe course of the disease, with fast reduction in steroid dosage. CONCLUSIONS: The findings demonstrate both the ability of the IFN-gamma release test to identify drugs that can induce pemphigus, and its usefulness in the diagnostic workup of pemphigus patients.

Unilateral spiny hyperkeratosis: case report and review of the literature.

We describe the first case of unilateral spiny hyperkeratosis (SH) of the left hand, review the literature and discuss possible patho- mechanisms. SH can be sporadic or familial, often appearing in healthy individuals. However, there is an association with various malignancies in a significant number of the sporadic cases. Although there is no satisfactory explanation of this association, we agree with previous authors that a patient with SH appearing in adult life should be evaluated and followed for the presence of malignancy. Other patients with SH may suffer from a variety of nonmalignant diseases, which may be coincidental or causally related. SH is not a premalignant lesion of the skin and should not be confused with porokeratosis which has a malignant potential. Except for excision of individual lesions, there is no permanent cure.