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Literature Review – October 2022
John Browning, MD
Secukinumab significantly reduces inflammation but only mildly improves scaling in four cases of Autosomal Recessive Congenital Ichthyosis.
Journal: Clinical and Experimental Dermatology
Publication Type and Date: Case Series. 2022 Aug 12. doi: 10.1111/ced.15373. Online ahead of print.
Reference: Subramani D, Sardana G, Kothari R, Gupta A.
Review: Autosomal recessive congenital ichthyosis parentheses (ARCI), consisting of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI), harlequin ichthyosis, and pleomorphic ichthyosis, is difficult to manage. In this article the authors share about their experience using secukinumab and treating three patients with ARCI. They were inspired to do this because of recent reports demonstrating elevation of IL-17 related cytokines in individuals with ARCI and reports of successful use of used to secukinumab in patients with CIE and Netherton syndrome. Secukinumab is a biologic that inhibits IL-17 and is FDA-approved as a treatment for psoriasis. The authors found that two siblings with CIE demonstrated dramatic improvement with secukinumab whereas the patient with LI only observed a modest improvement in scaling. They hypothesize that the improved results with the CIE patients are due to the presence of greater inflammation and elevated cytokine levels in CIE compared with LI.
Summary: Off-label use of secukinumab may be beneficial in treating CIE. More research is needed to evaluate optimal dosing, safety monitoring, and use in other forms of ichthyosis.
Management of Harlequin Ichthyosis: A Brief Review of the Recent Literature.
Journal: Children (Basel).
Publication Type and Date: Review. 2022 Jun 15;9(6):893
Reference: Tsivilika M, Kavvadas D, Karachrysafi S, Sioga A, Papamitsou T.
Review: Harlequin ichthyosis (HI) is a severe and extremely rare form of congenital ichthyosis. HI occurs mostly from mutations in the ABCA12 gene. There are three distinct types of HI, based mostly on skin abnormalities. Lipid dysregulation and severe desquamation lead to skin fractures and fissures due to significant lack of connective substance.
Admission to a NICU for newborns with HI is highly recommended as mortality is high, with average survival rate being 55%. HI's highest mortality rates were reported in the first three months of life due to respiratory failure or sepsis in 75% of cases. Affected neonates should be maintained in an incubator with additional humidity and constant monitoring of the kidneys and liver. Electrolytes, daily weight, and urine output should be monitored regularly. It is also crucial to prevent infection during this period.
Necrosis of neonatal digits is common and the application of a topical retinoid such as tazarotene cream 0.1% can help in prevention. If joint constriction or eclabium interferes with normal oral feeding then a nasogastric or oropharyngeal tube maybe placed for feeding. Once sucking and swallowing functions return then normal feeding can be resumed. Vitamin D levels should be monitored and possible supplementation may be necessary for management.
Ophthalmic ointment should be applied around the eyelid margin. Although surgical intervention has been reported for ectropion in the infantile period, there is no evidence that early surgery decreases the possibility for ectropion later in life. Systemic retinoid use is somewhat controversial and should only be considered under close guidance. Surgery can be difficult in this population due to vascular access and airway security issues. Surgical release of limb contraction may be necessary, especially in cases of compartment syndrome.
Parent cooperation is critical so as to avoid serious predicaments.
Summary: It is important for neonates with HI to be treated by physicians aware of the guidelines in managing the various and numerous issues that arise early in life so as to avoid further complications. Management requires a multidisciplinary team of experts in order to minimize risks and promote healthy outcomes.
Distinct skin microbiome community structures in congenital ichthyosis.
Journal: British Journal of Dermatology
Publication Type and Date: Original Investigation, 2022 May.
Reference: Tham KC, Lefferdink R, Duan K, Lim SS, Wong XFCC, Ibler E, Wu B, Abu-Zayed H, Rangel SM, Del Duca E, Chowdhury M, Chima M, Kim HJ, Lee B, Guttman-Yassky E, Paller AS, Common JEA.
Review: Although most forms of ichthyosis share a Th 17 cell immune signature, it is unknown and little research has been done in exploring the microbiota of ichthyosis. In this study, the authors analyzed the skin microbiome of participants with loss-of-function mutations in ALOX12B (CIE), CYP4F22 (CIE), NIPAL4 (CIE), PNPLA1 (CIE), TGM1 (LI), KRT10 (EI), and SPINK5 (NS). It was found that a dysbiosis of the skin microbiome occurred in all of these conditions, with higher abundance of staphylococci and corynebacterium, but lower abundance of C.. acnes. Microbiome analysis also showed increased abundance of M. sloofiae and Trichophyton species, implicating fungal species as part of the dysbiosis. The authors speculate that in the future biotherapeutics could play a part of the treatment strategy for ichthyosis.
Summary: The microbiome of ichthyosis skin is different from non-ichthyosis skin It is important to be aware of some of the specific differences so that anticipation of potential infections can be achieved. Use of topical probiotics might play a role in mitigating microbiome dysbiosis in the future.
Literature Review - August 2022
Robert A. Silverman, MD
"Big Data" Exposes Issues Linked to X-linked Ichthyosis
Reference: Brcic L, Wren GH, Underwood, FG, et al: Comorbid medical issues in X-linked ichthyosis. JID innovations 2022;2:100109
Review: X-linked ichthyosis occurs primarily in males, although mothers of these boys who carry the abnormal gene deletion on the X (female) chromosome can also show signs and symptoms of dry skin and more. The gene codes for a protein enzyme, steroid sulfatase (STS), that is important for skin integrity and many other important functions of other organs in the body. "Comorbidity" is the word that describes these other medical issues.
Different deletions in the same STS gene can cause different associated comorbidities. Boys may be born with undescended testicles, asymptomatic eye issues called corneal opacities, and neurodevelopmental or mood disorders. Young pregnant women who carry abnormalities in some of their genes have lower placental estrogen hormone that can result in longer gestations beyond term and delayed or prolonged labor. They also have milder dry skin and milder mood disorders.
Ichthyosis investigators in England analyzed a large United Kingdom databank containing medical information on over 500,000 middle-aged individuals from the general population. They uncovered new associated medical conditions in small numbers of affected adults that include heart problems, increased bleeding disorders such as nose bleeds, and placental hematomas in pregnant women. They also discovered an increased risk of palmar fascial fibromatosis also known as Dupuytren contracture. Exactly how the abnormal STS gene is related to these observations is not completely understood.
Patients with X-linked ichthyosis should know about newly discovered comorbidities and inform their primary care physician to be on the lookout for them.
Don't Forget Your Vitamin D
Reference: Bakshi S, Mahajan R, Karim A, et al: Oral vitamin D versus acitretin in congenital non-syndromic ichthyosis: double blinded, randomized controlled trial.
Review: Vitamin D is very important for day-to-day maintenance of your skin. It regulates cellular proliferation, differentiation, barrier function and immune function – all processes that are affected in patients with most, if not all, forms of ichthyosis. Because there is such a rapid production or turnover of skin cells in ichthyosis, it should not be surprising that vitamin D levels are frequently reduced.
There has been an interest in studying the role of vitamin D in ichthyosis for many years. Researchers performed a controlled, evidence-based evaluation of vitamin D administration in presumably non-vitamin D deficient children with ichthyosis and compared their findings to a similar group of children who were given acitretin, a retinoid that has been used for years for treating ichthyosis. They measured their results with several important validated scales, Visual Index for Ichthyosis Severity (VIIS), the Ichthyosis Area Severity Index (IASI) and the Ichthyosis Quality of Life Indes-32 (IQoL-32). They also measured the effects of vitamin D on important cellular pathways in the laboratory and looked for adverse events in the trials.
Subjects that were vitamin D deficient before the study were "normalized" with 60,000 IU vit D given eight weeks before the study began. For the 24-week study, subjects were given either vit D (2,000 iu/day) and an acitretin placebo or low-dose acitretin (.5mg/kg/day) and a vit D placebo.
While both groups improved in clinical parameters, there were no statistically significant differences in improvement between the vit D group when compared to the acitretin group. No serious adverse events occurred in any subject. In the lab, mRNA expression for IL-17 and the retinoid receptor gamma were both significantly reduced. The authors suggested that vitamin D and acitretin both work by the same mechanisms. They interpret these results as vitamin D is as good as acitretin for patients with ichthyosis.
Careful analysis of the study methods could uncover biases that led to these conclusions. Even though the results were mixed, vitamin D is very important and one should consider supplementation for all forms of "red" ichthyosis to keep levels in the normal range.
Interviews Assess Weight of Ichthyosis Caregiving
Reference: Daae E, Feragen KB, Sitek JC, von der Lippe C: It's more than just lubrication of the skin: parents' experiences of caring for a child with ichthyosis. Health Psychol and Behav Med 2022;10:335-356.
Review: Researchers from Norway have highlighted and confirmed the troubles, challenges and devastating effects that having a child with ichthyosis has on one's personal and family life. They sought to understand from the parents perspective, the issues that parents confront on a daily basis in order to provide information that would provide other clinicians and researchers, data to help parents manage stress and lead to better health outcomes for their children with ichthyosis.
The authors used semi-structured interviews, predetermined open-ended questions, and participant-led explorations to gather their findings. Participants in the study came from the Norweigan national database of rare disorders and included parents of children and adults with ichthyosis. There were a total of 19 parents and 19 children who participated in the study (48% of parents and 11% of adults in the total population of the patients with ichthyosis in the rare disease database. Interviews were by telephone which may have hampered the effects of nonverbal and visual cues on data collection but may have improved honest collection because of the sense of anonymity this technique provided.
Results were not surprising. There were four main themes: The reactions of new parents and others to the differences in their child's skin; experiences with health-care services; the difficulties of skin care; and, the impact on relationships. Parents of newborns felt afraid, alone, helpless and in denial. The lack of knowledge of health-care professionals, the lack of guidance and poor communication only served to magnify these distressing feelings. Touching, itching, pain, financial and time burdens were universally mentioned. Overwhelming emotions frequently resulted in poor communication about their worries in even every-day situations.
I recommend that this article be made available to all parents with a child who has ichthyosis and should be provided to, and read by, all of their health care providers to enhance their understanding of the effects of this condition.
Literature Review - January 2022
Leslie Potter Lawley, MD
Kerrie Satcher, MD
Prenatal diagnosis of a rare variant of harlequin ichthyosis with literature review
Journal: BMC Medical Imaging
Publication Type and Date: Case report and review of the literature, March 2021
Reference: Zhou Y, Liang L, Wang L, Zhang.
Harlequin ichthyosis (HI) is a rare ichthyosis that presents as large, plate-like scales covering the whole body, along with turned out lips (eclabium), turned out eyelids (ectropion) and flattened ears. There is rarely effective treatment for HI and mortality of affected patients is high. The authors report two cases of HI diagnosed with ultrasound during the third trimester. In case one, a 31-week ultrasound revealed thickening of the skin, ectropion, short nose bone, flat nose, open mouth and persistent flexion of the fingers and toes. In case two, a 30-week ultrasound, performed because of decreased fetal movements, showed similar findings.
The authors of this article reviewed the published literature over the past 20 years and found 10 cases of HI diagnosed through ultrasound. Three were identified during the second trimester and seven during the third trimester. Both 2D and 3D ultrasound used together best identify the features of HI. The characteristic features of HI on ultrasound will be apparent later in pregnancy and many pregnant women do not have an ultrasound during this latter part of gestation, when these features are evident.
Fetal characteristics of HI appreciated on ultrasound include ectropion, abnormal double auricles, flattened nasal ridge, persistent open mouth, limb contractures and decreased movement. Additionally, the authors comment that particles floating in the amniotic fluid can be seen. Both 2D and 3D ultrasound performed together later in pregnancy are most likely to identify these features.
Collodion babies: A 15-year retrospective multicenter study in The Netherlands- Evaluation of severity scores to predict the underlying disease.
Journal: Journal of the American Academy of Dermatology
Publication Type and Date: Research letter, April 2021
Reference: Cuperus E, Bolling M, Graaf M, et al.
Collodion baby can be the initial presentation in many different types of ichthyoses. A previous study by Rubio-Gomez et al proposed a clinical scoring system based on 15 characteristics of collodion. This previous study suggested extensive collodion was more associated with non-syndromic ichthyosis. The four major forms of non-syndromic ichthyosis include ichthyosis vulgaris, recessive X-linked ichthyosis, kertinopathic ichthyosis and autosomal recessive congenital ichthyosis.
The authors used the same collodion severity scoring system to evaluate 23 babies at three academic sites in the Netherlands. Genetic studies were completed on all babies and they were grouped into non-syndromic ichthyosis, syndromic ichthyosis, and self-healing collodion baby/unspecified congenital ichthyosis. The authors found no significant difference in the scores of the syndromic and non-syndromic ichthyosis groups. Although, the authors did find a trend toward lower severity scores in the syndromic ichthyosis group.
A scoring system has been proposed as a way to measure severity of collodion and predict the underlying ichthyosis type. This scoring system has not been proven to reliably predict type of ichthyosis, although, lower scores have been seen in syndromic ichthyosis and higher scores in non-syndromic ichthyosis. It is possible that the small number of study patients contributed to the inability to assess the validity of the scoring system.
The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.
Journal: Journal of the American Medical Association Dermatology
Publication Type and Date: Original investigation, December 2021
Reference: Sun Q, Burgren N, Cheraghlou S, et al.
Over a 10 year period, the authors recruited 1000 patients from all over the world with ichthyosis to be a part of the study. Patients completed a questionnaire, genetic testing on blood or saliva, and standardized clinical photographs. Pathogenic variants of genetic material were identified in 869 participants. The authors identified 266 unique disease associated variants in 32 genes.
35% of patients with a genetic diagnosis completed the questionnaire. Itching, decreased sweating, skin pain, eye problems, skin odor and infections were the most commonly reported features.
Collodion membrane at birth, skin odor, hearing problems, eye problems and alopecia were associated with patients who had TGM1 variant.
Collodion membrane at birth was associated with patients who had ALOX12B variant.
Skin pain, skin odor and skin infections were associated with patients who had KRT10 variant.
Collodion membrane at birth and skin odor were associated with patients who had FLG variant.
Collodion membrane at birth, skin pain, skin odor, skin infections, and hypohidrosis were associated with patients with STS variant.
This study helps us expand the genetic causes of ichthyosis, along with the clinical features of different types of ichthyoses. The authors report specific clinical features of ichthyosis which are significantly associated with particular genetic causes. This can help doctors with diagnosis, and guide treatment plans for patients moving forward.
Literature Review - June 2021
Dr. Erin Mathes
Dr. Mitchell Braun
Inherited ichthyosis and fungal infection: an update on pathogenesis and treatment strategies
Journal: Journal of the German Society of Dermatology
Publication Type and Date: Systematic review article, March 2021.
Reference: Miao H, Dong R, Zhang S, et al. Inherited ichthyosis and fungal infection: an update on pathogenesis and treatment strategies. J Dtsch Dermatol Ges. 2021.
People with ichthyosis may have a higher risk of developing skin fungal infections compared to the general population. Authors of this article reviewed cases of fungal infections in ichthyosis over the past 50 years to summarize the causes, signs and symptoms, diagnosis, and treatments. The increased risk of fungal infections in ichthyosis is likely multifactorial. In ichthyosis mutated proteins alter the skin's "barrier function", decreasing its ability to keep out organisms like bacteria and fungi. At the same time, in some forms of ichthyosis, such as KID (keratitis, ichthyosis, and deafness), cells that fight infection in the skin are missing or dysfunctional. Lastly, abnormal keratin production and impaired skin cell turnover in ichthyosis may also create a unique environment in which some fungi thrive.
It can be difficult to identify skin fungal infections in people with ichthyosis due to dry or scaling skin, itchiness, or redness at baseline. Importantly, fungal infections tend to present with new alopecia (hair loss), papules (bumps), pustules (bumps with pus), or worsening of scaling especially in warmer summer months. Both ichthyosis and fungus can also lead to yellow, thick and brittle nails. In cases of fungal infection, these changes tend to be new and affect fewer nails, sometimes only one. Treatment options include both topical and oral antifungal medications. In some people with ichthyosis, infections may be severe or recurrent, and a combination of topical and oral medications are preferred.
People with ichthyosis have more fungal skin infections than the general population and diagnosis can be difficult. Fungal infections should be considered in new or worsening hair loss, bumps, pustules, worsening scale, or changes to nails. If any of these symptoms arise, people with ichthyosis should discuss them with their primary care doctor or dermatologist.
Use of telemedicine for ichthyosis: patient advocacy group as conduit to expert physician advice
Journal: Pediatric Dermatology
Publication Type and Date: Retrospective cohort study, January 2021.
Reference: Asch S, Swink SM, Vivar KL, et al. Use of telemedicine for ichthyosis: Patient advocacy group as conduit to expert physician advice. Pediatr Dermatol. 2021.
The FIRST Tele-Ichthyosis program began in 2009 and allows for physicians around the world to refer cases of known or possible keratinizing disorders to a group of peer and patient-selected volunteer ichthyosis experts. The goal is to increase access to care for patients who may struggle to find local expertise of these rare conditions. The authors reviewed the strengths, limitations, and use of this program over the past decade. The expert panel reviewed a total of 88 cases since the program's inception from the United States, Canada, the Caribbean, South America, Europe, Africa, Asia, and the Middle East. The number of cases has increased over the years since inception. The submitting physicians requested insight into treatment, diagnosis, and genetic testing information. The volunteer panel diagnosed ichthyosis in 66% of cases that were reviewed. About 2/3 of submitting physicians described the service as easy to use and reported timely, clear, and beneficial advice. A re-design is underway to maximize the usability of the site. Expert advice obtained through the Tele-Ichthyosis program aided longitudinal care, as submitting providers shared advice during transitions of care to clinicians and caregivers.
Some people with ichthyosis do not have local access to expert opinion. The FIRST Tele-Ichthyosis program provides these patients and their local providers with insights from a panel of ichthyosis experts. This program will continue providing advice on diagnosis, treatment, and other aspects of keratinizing disorders and serves as an example of how telemedicine can benefit treatment and care across the world for rare diseases.
Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents
Publication Type and Date: Consensus recommendations, January 2021
Reference: Zaenglein AL, Levy ML, Stefanko NS, et al. Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents. Pediatr Dermatol. 2021.
Retinoids are vitamin A derivatives that work to reduce scaling and thickening of the skin in many ichthyoses and are essential to management. A group of expert physicians from the Pediatric Dermatology Research Alliance (PeDRA) convened to address the use of both topical and systemic retinoids in ichthyoses and other disorders of cornification. The impact of long-term retinoids on bone, eye, reproductive and psychiatric health were reviewed with the goal of creating recommendations for drug dosing and monitoring. Specific considerations and guidelines are outlined in the paper, and individuals taking systemic retinoids should work with a provider who is familiar with retinoids and disorders of cornification to minimize side effects.
Overall, the likelihood of side effects depends on many factors and tends to occur after long periods of use. The benefits of systemic retinoids in treating ichthyoses often outweigh the risks, and they should always be considered if topical therapies do not provide sufficient improvements, the burden of disease is high, or if there is a significant impact on quality of life. Proper monitoring while on systemic therapy will decrease the risk of unidentified side effects. Research will continue to improve our understanding of retinoids' effects on the body. Updated consensus recommendations will follow as additional research is produced.
Topical and systemic retinoids are recommended for the treatment of ichthyoses and other diseases of cornification. The benefits of systemic retinoids often outweigh the risks, and regular monitoring for side effects is an effective measure in preventing long term impacts of these medications.
Increased risk of depression and impairment in quality of life in patients with lamellar ichthyosis
Journal: Dermatologic Therapy
Publication Type and Date: Cross sectional; January 2021.
Reference: Cortés H, Rojas-Márquez M, Reyes-Hernández OD, et al. Increased risk of depression and impairment in quality of life in patients with lamellar ichthyosis. Dermatol Ther. 2021.
Lamellar icthyosis (LI) is one of the most severe clinical phenotypes of ichthyosis and is characterized by thick plate-like scales, itch, pain, alopecia (hair loss), and erythema (redness). This disease has been shown to negatively impact quality of life (QoL). In this study, the investigators identified 26 people with LI and 26 healthy controls from Mexico and used the Depression Beck Inventory II (DBI-II) and Dermatologic Life Quality Index (DLQI) to assess depression and impairment in QoL between the two groups. The Congenital Ichthyosis Severity Index (CISI) was used to determined severity of LI at the time of the surveys. There was a significant difference in DBI-II scores between people with LI and healthy volunteers, indicating higher levels of depression in people with LI. When factoring in the severity of LI using the CISI, there were no differences in levels of depression or impairments to QoL between mild or severe disease. Those with high levels of depression documented larger impairments in QoL. Although this study had a small number of patients, it highlights the impact that LI can have on mental health and to what extent it can impact quality of life, even in mild disease severity. It suggests the importance of mental healthcare in maximizing health and wellbeing in people with LI.
LI is associated with higher rates of depression when compared to healthy controls and has a significant impact on quality of life regardless of disease severity. Mental healthcare is an important aspect of LI healthcare, and there should be regular discussions about mental health and wellbeing.
Literature Review - October 2020
Mary Sun, BS
Keith Choate, MD, PhD
Yale School of Medicine, New Haven, CT
Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis
Journal: American Journal of Human Genetics
Publication Type & Date: Original article, July 2, 2020
Reference: Boyden LM, Zhou J, Hu R et al. Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis. The American Journal of Human Genetics 2020; 107: 158-63.
Review: Lamellar ichthyosis featuring palmoplantar keratoderma (PPK) had exclusively been attributed to autosomal recessive mutations prior to this discovery. Investigators sequenced the coding regions of all the genes in the genome to reveal that in four unrelated ichthyosis kindreds, ten subjects with ichthyosis and PPK had heterozygous, novel missense mutations in ASPRV1 causing autosomal dominant ichthyosis. The mutations arose in utero in two individuals, and mutations in the other eight subjects were transmitted from one generation to the next, indicating that ASPRV1 mutations cause a dominantly inherited ichthyosis that was previously known to have recessive inheritance. ASPRV1 encodes skin aspartic protease, an enzyme that breaks down the filaggrin protein. Compared to age-matched controls, those with ASPRV1 mutations have excess unprocessed filaggrin protein and epidermal differentiation impairment resulting in thick scale and PPK. Given this desquamation defect, keratolytic agents can prove therapeutically beneficial, as two affected individuals who used keratolytics experienced complete resolution of non-palmoplantar scale.
Summary: ASPRV1 mutations cause dominantly-inherited lamellar ichthyosis with palmoplantar keratoderma, highlighting the importance of aspartic proteases (enzymes that break down filaggrin protein in the skin) in epidermal differentiation. This not only further elucidates the various causes of ichthyosis but also provides a potential target for future therapies.
3D Model of Harlequin Ichthyosis Reveals Inflammatory Therapeutic Targets
Journal: Journal of Clinical Investigation
Publication Type & Date: Original article, Aug 10, 2020
Reference: Enjalbert F, Dewan P, Caley MP et al. 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets. The Journal of Clinical Investigation 2020; 130: 4798-810.
Review: Harlequin ichthyosis (HI) is a rare, severe ichthyosis with high rates of complications and death in the perinatal period. It is caused by mutations in the gene ABCA12 which eliminate or severely reduce the function of its encoded protein. Skin inflammation is a well-known component of HI but few studies have investigated the inflammatory processes inherent in the disorder. The authors developed a 3D model of HI using CRISPR/Cas9 (a technique that edits the genome) to engineer an ABCA12 knockout cell line that closely mimicked the most severe HI phenotype. Using this model and HI skin samples, the authors discovered upregulation of cytokines in the IL-1 family and upregulation of the STAT1/NOS2 signaling pathway, which results in increased accumulation of inflammatory free radicals. Inhibition of NOS2, an enzyme with a central role in inflammatory processes, reversed the barrier defects seen in the HI model. These findings not only provide insight into the pathogenesis of HI but also reveal new therapeutic targets.
Summary: Upregulation of inflammation, in particular proinflammatory cytokines, STAT1 and NOS2 signaling drives HI redness.
Malnutrition in children with ichthyosis: recommendations for monitoring from a multidisciplinary clinic experience
Journal: JAAD
Publication Type & Date: Original article; June 2020
Reference: Rodríguez-Manchón S, Pedrón-Giner C, Cañedo-Villarroya E et al. Malnutrition in children with ichthyosis: recommendations for monitoring from a multidisciplinary clinic experience. Journal of the American Academy of Dermatology 2020.
Review: Growth failure (not meeting milestones for height and weight among other measures) is common among individuals with congenital ichthyosis but there is a paucity of data evaluating nutritional status in ichthyosis. The authors assessed 50 ichthyosis patients, majority of whom were male and under 18 years of age, in a prospective study at a hospital in Spain. Nearly one-third met WHO criteria for undernutrition. Growth impairment was found in 24% of children, especially those 5 years and younger. Ichthyosis severity positively correlated with rates of undernutrition, and nearly two-thirds of patients had micronutrient deficiencies, particularly deficits in iron, selenium, vitamin D and zinc. These results provide the rationale for early nutritional assessment and support in order to maximize growth potential.
Summary: Children, especially those who are younger and those with severe ichthyosis, are at risk of malnutrition and should have nutritional assessment at diagnosis and during follow-up.
Edited by Emily Henkel, MD, MPH
Dell Medical School, Austin, TX
Secukinumab Therapy for Netherton Syndrome
Journal: JAMA Dermatology
Publication Type & Date: Case Series; May 2020
Reference: Luchsinger, Isabelle, et al. "Secukinumab Therapy for Netherton Syndrome." JAMA Dermatology. PMID: 32459284 DOI: 10.1001/jamadermatol.2020.1019
Review: Previous research has demonstrated increased activity of the helper T cell 17/interleukin 23 pathway in patients with Netherton Syndrome. When activated, these cells release IL-17, which stimulates skin cells (keratinocytes) to proliferate. A medication commonly used for psoriasis, secukinumab (Cosentyx®) is designed to stop this signal. This case series evaluated the efficacy of using secukinumab to treat four patients with Netherton Syndrome. Significant improvement in ichthyosis area, severity, itch, and quality of life was seen in all patients by three months and was measured using established scales (Ichthyosis area and severity index, 5-D itch scale). The best results were seen in the two pediatric patients with the erythrodermic subtype. Three patients were followed for 6-12 months and all chose to remain on the medication. The only side effects experienced during this time were nail fungus infection and an itchy eczema reaction on the palms. This research shows promise that this medication may be beneficial to Netherton Syndrome patients with severe erythema and itch and should be investigated further with more patients over a long period of time.
Summary: For patients with Netherton Syndrome and severe itch and diffuse redness (erythroderma), a treatment option can be considered, as noted, in the summary above.
Ichthyosis affects mental health in adults and children: A cross-sectional study
Publication Type & Date: Research Letter (in press); Jan 2020
Reference: Sun, Qisi, et al. "Ichthyosis affects mental health in adults and children: A cross-sectional study." Journal of the American Academy of Dermatology (2020).
PMID: 32006604 DOI: 10.1016/j.jaad.2020.01.052
Review: Patients with ichthyosis face daily challenges that may include discomfort, harassment, and difficulty engaging in work or leisure activities as a result of their disorder. This study surveyed 181 patients from the National Ichthyosis Registry to investigate the psychiatric impact of the disorder. The patients were surveyed using questionnaires (PHQ-9, GAD-7) commonly utilized to screen for anxiety, depression and quality of life in patients with other medical conditions. The results showed that among adults with ichthyosis, 34% screened positive for depression, 27% positive for anxiety, and 95% experienced impairment in their quality of life. The results were similar in the pediatric population with 30% positive for depression, 38% positive for anxiety, and 85% with quality of life impairment. Most participants surveyed had the autosomal recessive congenital ichthyosis (ARCI) subtype and the results did not differ significantly between those with severe versus those with moderate disease severity. These data highlight the need for physicians to screen ichthyosis patients in order to detect any psychologic sequelae and provide appropriate care.
Summary: As known by many patients and families impacted by any type of ichthyosis, the potential impact on personal interactions and behavioral differences cannot be overlooked. While formal screening for, for instance, depression (as done in this study) can be considered, from a practical stance, such information should be sought from patients and/or family members when evaluating our patients.
Association of the Severity of Alopecia with the Severity of Ichthyosis
Publication Type & Date: Research Letter; Sept 2019
Reference: Putterman, Elana, et al. "Association of the Severity of Alopecia With the Severity of Ichthyosis." JAMA dermatology 155.9 (2019): 1077-1078.
PMID: 31365037 DOI: 10.1001/jamadermatol.2019.1520
Review: Hair loss (alopecia) is commonly reported in patients with ichthyosis, but not much is known about why this happens or if it is associated with a particular subtype or severity of ichthyosis. This small study was conducted with 86 patients from the National Registry for Ichthyosis and Related Skin Types to investigate if hair loss can be predicted based on disease severity or the genetics related to subtypes. In this study, two experts examined photographs of each patient without knowing their genetic subtype and scored the severity of hair loss and skin findings. The results showed that there was no significant relationship between the severity of skin findings and hair loss severity. However, when they separated the patients by genetic subtype, those with TGM1 and ABCA12 mutations appeared to have more severe hair loss in association with their greater skin disease severity. While previous research has shown the association of hair loss with TGM1 mutation, these results suggest that ABCA12 mutation may also be associated with hair loss in milder phenotypes in addition to the known association of severe hair loss in those with harlequin ichthyosis. Additionally, patients in these subtypes may suffer from more severe hair loss if they have severe skin symptoms than patients in these subtypes with more moderate skin findings.
Summary: While ichthyosis can, in some cases, be associated with hair loss or alopecia, there does seem to be relationship with more severe types of disease as noted by most physicians caring for these patients and by the patients, themselves. The authors seem to confirm the relationship with certain genetic mutations which can be associated with more severe disease, overall, as well as in some of the milder clinical subtypes.


The test program announced Thursday could make Kroger the first U.S. grocer to make deliveries with robotic cars that won't have a human riding along to take control in case something goes wrong.
Customers will be able to order groceries from a mobile app, much like people summon an Uber or Lyft ride. After the order is place, a driverless vehicle will deliver the groceries at a curb, requiring the customers to be present to fetch the items. The vehicles will probably be opened with a numeric code.
Kroger currently offers grocery delivery in vehicles driven by people at about 1,200 of its 2,800 stores, covering about 20 different markets in the U.S. If the Nuro tests go well, Kroger say it's likely to expand its use of driverless cars, potentially allowing its supermarkets to reduce its delivery fees and reassign workers who had been driving cars to other jobs focused on improving customer service.


text:
Ugarska voda (franc. l'eau de Hongrie), larendogra (franc. (l'eau de) la reine d'Hongrie: (voda) ugarske kraljice) ili voda ugarske kraljice (lat. aqua reginae Hungaricae) bio je prvi (europski) parfem baziran na alkoholu, a potječe iz kasnog 14. stoljeća. Prema legendi prvi je put formuliran na zapovijed ugarske kraljice koja se katkad naziva Izabelom, iako se obično navodi kao Elizabeta, odnosno u jednom dokumentu "sveta Elizabeta, kraljica ugarska" (ovo može biti konflacija mnogih pojedinaca). Ove legende, i dokumentirane referencije o njegovoj pripremi, uglavnom potječu do ranih godina sredine 17. stoljeća, pa detalji koji potječu iz naknadnih stoljeća mogu dovesti do zbrke.

Kraljica o kojoj je riječ često se pretpostavlja da je Elizabeta Poljska (1305. – 1380.) iako se pojedini detalji njezina života ne podudaraju s onima iz najčešćeg prikaza legende; još je nevjerojatnije da bi to mogla biti sveta Elizabeta Ugarska (1207. – 1231.) koja osim što je živjela prerano nije ni bila kraljica (valja primijetiti da je tehnika destilacije postala dobro poznata u Europi tek oko 1150. do 1250.). Jedina prihvatljiva kraljica Elizabeta (kasno 13. stoljeće) čini se jednako tako preranom da bi bila čvrstom kandidaticom.

Točan datum pronalaska ugarske vode izgubljen je u povijesti. Jednako je nejasno tko ju je točno stvorio. Neki izvori kazuju da je to bio neki zatvoreni redovnik koji ju je prvi dao Elizabeti iako ju je najvjerojatnije izradio dvorski alkemičar (koji je također mogao biti redovnik, time pomirivši ove dvije tradicije). Najstariji sačuvani recepti nalažu destilaciju svježa ružmarina (i vjerojatno majčine dušice) s jakim vinjakom dok naknadne formulacije sadrže lavandu, metvicu, kadulju, mažuran, kostus, narančin cvijet i limun.

S obzirom na same legende ugarska se voda prvi put pojavila izvan Ugarske 1370. godine kada ju je dobio francuski kralj Karlo V. Mudri, slavan po svojoj ljubavi prema mirisima.

Ugarska je voda bila poznata diljem Europe tijekom mnogih stoljeća, a sve do pojave kolonjske vode u 18. stoljeću bila je najpopularniji miris i lijek u uporabi. Slično ostalim biljnim i cvjetnim proizvodima ugarska vodica nije bila samo puki (ili čak glavni) miris nego i vrijedan lijek; rani recepti savjetuju da se korisnik njome pere, ali i da je pije radi postizanja najveće koristi od nje.

Iako je bio vrlo rašireni srednjovjekovni lijek, i danas se rabi, pogotovo kao parfem. Kraljici sv. Elizabeti Ugarskoj, kojoj ga srednjovjekovna legenda pripisuje, služio je za ljepotu te masiranje paraliziranih udova i gihta od kojih je bolovala kraljica pred kraj života. Prema legendi, mađarska kraljica Elizabeta Ugarska bolovala je od gihta i reume, ali je bolest uspjela izliječiti parfemskom vodicom od destilata ružmarina, lavande i metvice (prema nekim autorima sastav je ružmarin, cedar i terpentin). Vodicu je upotrebljavala i u kozmetičke svrhe, pa je uspjela toliko pomladiti lice i tijelo da ju je u njezinoj 72 godini zaprosio mladi poljski kralj. Ta čuvena parfemska vodica predstavljena je europskoj eliti 1370. u Parizu na dvoru Karla V. Mudrog.

Priprema

Prirema se tinktura od ružmarina i na isti način tinktura od lavande; tri dijela tinkture od ružmarina se primiješa jednom dijelu tinkture od lavande (unutarnja primjena: mala žličica na dan – samo za odrasle, vanjska primjena: za trljanje, masažu, protiv reume, uloga, raznih bolova). Tinkture su tekući alkoholni ekstrakti iz ljekoviti biljaka. Za tinkture se upotrebljava 40, 50 ili 70-postotni alkohol.

Izvori

kozmetika
biljni ekstrakti i pripravci

redpajama_set_name: RedPajamaWikipedia


text:
De zaak-Dutroux was een geruchtmakend onderzoek en rechtszaak in België in en na de jaren 90 van de vorige eeuw rond de crimineel Marc Dutroux en zijn, bij de door hem gepleegde misdrijven als handlanger aangemerkte, vriend Michel Lelièvre. Dutroux stond zelf terecht op verdenking van ontvoering, gijzeling, verkrachting, moord en illegale handel en is veroordeeld tot levenslange opsluiting en terbeschikkingstelling van de regering.

Op 15 augustus 1996 werd de zes dagen tevoren ontvoerde minderjarige Laetitia Delhez in zijn huis ontdekt, samen met Sabine Dardenne, die al bijna drie maanden opgesloten zat in de woning. Al snel bleek dat Dutroux ook verantwoordelijk was voor de ontvoering van Julie Lejeune, Mélissa Russo, An Marchal en Eefje Lambrecks, die allen dood werden teruggevonden. Daarnaast had hij ook de dood van zijn handlanger Bernard Weinstein op zijn geweten.

Verdachten
In het proces stonden naast hoofdverdachte Marc Dutroux zelf de volgende personen terecht:

 Michelle Martin, de ex-echtgenote van Dutroux;
 Michel Lelièvre, een vriend van Dutroux;
 Michel Nihoul, een zakenman en zakenpartner van Dutroux.

Slachtoffers

Julie en Mélissa
Julie Lejeune (29 november 1987) en Mélissa Russo (11 september 1987), twee Waalse vriendinnetjes, werden op 24 juni 1995 samen ontvoerd in Grâce-Hollogne, een gemeente in de provincie Luik. De toen zevenjarige meisjes hadden samen nog op een brug over de autosnelweg gestaan om naar voorbijrijdende auto's te zwaaien. Op 17 augustus 1996 werden hun lichamen teruggevonden in de tuin van Dutroux' vrouw Michelle Martin in Sars-la-Buissière.

Dutroux werd beschuldigd van de moord, ondanks het feit dat hij dit altijd ontkende en beweerde dat de meisjes "hem gebracht werden" en dat hij ze dan opsloot.
Waarschijnlijk werd hij voor de ontvoering bijgestaan door een medeplichtige. Dat zou Bernard Weinstein geweest zijn, die later door Dutroux vermoord werd. Waarschijnlijk hebben Julie en Mélissa vanaf het moment van hun ontvoering nog ongeveer negen maanden in gevangenschap geleefd.

Gevangenschap en overlijden
De meisjes hebben samen opgesloten gezeten in een krappe cel, verborgen in de kelder van Dutroux' huis in Marcinelle, die speciaal was gebouwd voor de opsluiting. De toegang werd aan het oog onttrokken achter een zwaar houten rek vol conservenblikken en flessen. Waarschijnlijk vertelde Dutroux ook aan hen wat hij Sabine en Laetitia wijsmaakte: dat hij hen gered had uit de klauwen van 'de baas', en dat hun ouders heel goed wisten dat ze hier zaten maar het losgeld niet wilden of konden betalen.

Over de precieze doodsoorzaak is niet veel bekend. Waarschijnlijk kwamen zowel Julie als Mélissa om van honger en dorst, negen maanden na hun ontvoering. Dutroux was op 6 december 1995 gearresteerd en moest voor een tijd de gevangenis in. Hij had zijn vrouw Michelle Martin opgedragen voor de kinderen te zorgen, wat ze niet deed. Ze kwam wel de hond voeren, maar was naar eigen zeggen bang om de kelder in te gaan bij de kinderen.<ref>{{Citeer web |url=https://www.nieuwsblad.be/cnt/gei4auit |titel=Michelle Martin: ,,Leven met hem was erger dan de hel |datum=4 maart 2004 |bezochtdatum=2023-02-22 |werk=Het Nieuwsblad |taal=nl-BE}}</ref> Na zijn vrijlating in maart 1996 trof Dutroux naar eigen zeggen een schrijnend tafereel aan: het gelijkvloers lag vol ontlasting van de honden, terwijl de kelder bezaaid was met papieren zakdoeken. De meisjes bevonden zich in zeer verzwakte en ondervoede staat; Julie zou die dag gestorven zijn, en Mélissa vier dagen later. Volgens experts is het echter onmogelijk dat twee meisjes van amper acht jaar oud, die al verzwakt zijn door de vijf maanden opsluiting die ze al doorgemaakt hadden, nog eens vier maanden konden overleven zonder eten of drinken. Hoe en of ze echt die vier maanden van Dutroux' afwezigheid doorkwamen, weet niemand. Ze werden begraven in de tuin van Michelle Martin in Sars-la Buissière.

 Vondst Julie en Mélissa en nasleep
Op 17 augustus 1996, vier dagen na de arrestatie van Dutroux en twee dagen na de bevrijding van Sabine en Laetitia, werden de lichamen van Julie en Mélissa op aanwijzingen van Dutroux opgegraven.

De ouders van Julie en Mélissa uitten tijdens persconferenties en talrijke televisie-uitzendingen felle kritiek op het onderzoek naar de verdwijning van hun kinderen, onder andere op het gebrek aan betrokkenheid bij het onderzoek en de weigering aan de ouders om het dossier in te zien.

De foto van de twee meisjes ging ondertussen de hele wereld rond en ze werden in België het symbool van het lijden van Dutroux' zes slachtoffers. Hun gemeenschappelijke begrafenis op 22 augustus 1996 werd een officieuze dag van nationale rouw en legde het hele openbare leven in België plat. Julie en Mélissa liggen nu naast elkaar begraven op het kerkhof van Grâce-Hollogne.

In juni 1996 hoorde Julies vader, Jean-Denis Lejeune, over het National Center for Missing and Exploited Children in Washington D.C.. Hij besloot een gelijkwaardig project op te richten, specifiek voor België. Op 20 oktober 1996, de dag van de Witte Mars, legde hij zijn idee voor aan toenmalig eerste minister Jean-Luc Dehaene en vroeg zijn steun voor het opstarten. Op 31 maart 1998 werd het Europees Centrum voor Vermiste en Seksueel Uitgebuite Kinderen operationeel, onder de naam Child Focus.

 An en Eefje
De Vlaamse vriendinnen An Marchal (10 december 1977) en Eefje Lambrecks (3 januari 1976) werden in de nacht van 22 op 23 augustus 1995 bij Oostende ontvoerd na het bijwonen van een hypnoseshow van Rasti Rostelli. Omdat op videobeelden te zien was dat ze verward uit de show buitenkwamen, was die een tijdje verdachte.

Op 3 september 1996 werden hun lichamen teruggevonden onder een loods in Jumet bij Charleroi, naast een huis dat eigendom was van Dutroux. De lichamen werden gevonden op aanwijzen van Dutroux, nadat hij eerst de ontvoering van Laetitia Delhez en drie andere meisjes had bekend. Er is geen zekerheid over het tijdstip noch over de omstandigheden van hun dood.

 Vondst An en Eefje en nasleep
Op het optreden van de Belgische politie kwam veel kritiek, omdat de onderzoeksrechter pas twee weken na de ontvoering zou zijn ingelicht, en omdat er geen enkel verband werd gelegd met de ontvoering van Julie en Mélissa, twee maanden eerder. Er waren voldoende getuigen en andere aanwijzingen tot ongeveer 01.20 uur 's nachts, daarna "leek het alsof ze van de aardbodem verdwenen waren".

De Belgische politie had de homevideo's van Marc Dutroux al een jaar op het bureau liggen, maar had ze niet bekeken omdat er geen videorecorder voorhanden was. Op een van de video's was te zien hoe Dutroux de geheime kelder had gemaakt. Als de politie ze wél bekeken had, hadden An en Eefje wellicht nog gered kunnen worden. De verontwaardiging over de blunders in het onderzoek leidde tot de grootste demonstratie in de geschiedenis van het land: de Witte Mars.

De ouders van Eefje Lambrecks wensten geen ruchtbaarheid over de zaak en bleven zorgvuldig buiten de publiciteit, in tegenstelling tot de vader van An, Paul Marchal, met wie ze in botsing kwamen. An en Eefje werden niet samen begraven (in tegenstelling tot Julie en Mélissa). De rechtbank verbood Marchal tevens om een vzw 'An en Eefje' op te richten.

Paul Marchal zou een van de spilfiguren van de Witte Beweging worden. Zo richtte hij eind 1997 de kortstondige Partij voor een Nieuwe Politiek in België (PNPb) op, en zette hij het Huis van An op, een plaats waar kinderen met problemen terechtkunnen.

Lambrecks was de enige van de slachtoffers van Dutroux die ten tijde van de misdaad wettelijk meerderjarig was; vermoedelijk hierom is haar geboortedatum niet genoemd in de officiële aanklacht.

 Sabine en Laetitia
De Waalse meisjes Sabine Dardenne (28 oktober 1983) en Laetitia Delhez (25 november 1981) waren de laatste slachtoffers van de bende van Dutroux en de enige overlevenden. Dardenne werd op 28 mei 1996, op twaalfjarige leeftijd, ontvoerd toen zij op weg was naar school. Na 77 dagen gevangenschap kreeg zij gezelschap van de toen veertienjarige Delhez, die drie dagen daarvoor, op 9 augustus 1996, in Bertrix ontvoerd werd toen zij onderweg was naar huis na een bezoek aan het zwembad.

Op 15 augustus 1996 werden beide meisjes bevrijd door de Belgische politie. Dutroux was twee dagen eerder gearresteerd, en gaf toe hen beiden verkracht en misbruikt te hebben. De bevrijding kwam tot stand nadat enkele getuigen Dutroux en zijn busje hadden gezien tijdens de ontvoering van Laetitia. Enerzijds door een bewoner die vond dat de aftandse bestelwagen een hels kabaal maakte, en anderzijds door een student die een deel van de nummerplaat had onthouden.

Dardenne en Delhez getuigden beiden tegen Dutroux. Tijdens het proces vroegen zij hem waarom hij hen misbruikt en verkracht had. Sabine stelde rechtstreeks de vraag waarom Dutroux haar niet had vermoord. Sabine Dardenne publiceerde in 2004 een boek over de gebeurtenissen.

 Onderzoek
Het gedwongen vertrek van onderzoeksrechter Jean-Marc Connerotte, vanwege het spaghetti-arrest, leidde in het najaar van 1996 tot commotie. Connerotte had aan een benefietavond voor de ouders van vermiste kinderen deelgenomen en er een bord spaghetti gegeten en een vulpen gekregen. Dit was een overtreding van de onpartijdigheid die zijn functie vereiste en hij werd van de zaak gehaald. Het grote publiek wantrouwde politie en overheid, en toonde dat met een grote protestdemonstratie in Brussel, de zogeheten Witte Mars. Connerottes opvolger Jacques Langlois bleek een beginner; het onderzoek-Dutroux was zijn eerste zaak. Anders dan procureur Michel Bourlet geloofde hij niet dat Dutroux en medeverdachte Michel Nihoul betrokken waren bij een prostitutienetwerk. Het kostte Langlois bijna acht jaar om de zaak rond te krijgen: een record in de Belgische rechtsgeschiedenis.

De verklaringen van getuige X1 (Regina Louf) over een geheim netwerk waarin kinderen werden misbruikt en vermoord en waarvan Dutroux en Nihoul deel zouden uitmaken, werden onderzocht, maar er werden volgens het parket geen aanwijzingen gevonden dat haar verhaal op waarheid zou berusten. Het gerecht besloot dit spoor noch het spoor naar satanisch ritueel misbruik verder te volgen.

Marc Dutroux wist op 23 april 1998 kortstondig te ontsnappen. Dit kostte het ontslag van twee ministers (minister van Binnenlandse Zaken Johan Vande Lanotte en minister van Justitie Stefaan De Clerck) en van luitenant-generaal Willy Deridder, commandant van de rijkswacht. De boswachter die Dutroux ving, Stéphane Michaux, werd later ontvangen door de koning.

 Proces
Op 1 maart 2004 startte het proces tegen Marc Dutroux, zijn vrouw Michelle Martin, vriend Michel Lelièvre en zakenman Michel Nihoul. Het werd gehouden in Aarlen, omdat de zittingszaal van het Hof van Assisen niet voldoende plaats kon bieden aan de duizenden journalisten en andere belangstellenden voor -wat al snel genoemd werd- "Het proces van de Eeuw".

Hoofdverdachte Dutroux stond terecht voor de ontvoering en opsluiting van Julie Lejeune, Mélissa Russo, An Marchal, Eefje Lambrecks, Sabine Dardenne, Laetitia Delhez en zijn handlanger Bernard Weinstein, en tevens voor de moord op Bernard Weinstein en An en Eefje. Daarnaast werd hij aangeklaagd wegens de gijzeling van vier tieners in zijn vrachtwagen, verkrachting van de bovengenoemde meisjes en nog 3 andere meisjes, drugshandel, illegale autohandel, valse identiteitsbewijzen en diefstal met geweld. Deze misdaden werden in een apart proces behandeld.

Op de eerste dag werd uit 180 kandidaten de Jury gekozen: 12 leden en 12 reserve-leden. De akte van beschuldiging, die op de tweede dag wordt voorgelezen, besloeg 74 pagina's. Op 3 maart 2004 vonden de verhoren van de verdachten plaats. Dutroux bekende de ontvoering en verkrachting van An, Eefje, Sabine en Laetitia, maar verklaarde dat de ontvoering van Julie en Mélissa het werk van Michel Nihoul was. Ook ontkende hij de verantwoordelijkheid voor de dood van de meisjes. Hij beweerde slechts een klein radertje in een veel groter netwerk te zijn en in opdracht gehandeld te hebben. Volgens hem zouden agenten hem hebben meegeholpen bij de ontvoering van An en Eefje. Op 4 maart 2004 begonnen de getuigenverhoren. Naast onderzoeksrechter Connerotte werden ook de beide overlevende slachtoffers Sabine Dardenne en Laetitia Delhez gehoord. Beide meisjes verklaarden door Dutroux te zijn ontvoerd en langdurig te zijn vastgehouden en misbruikt. Sabine zat 81 dagen vast in een kleine ruimte in Dutroux' kelder.

Haar getuigenis staat beschreven in het boek Ik was twaalf en ik fietste naar school uit 2004. Ze weigerde nadrukkelijk de excuses van Michelle Martin te aanvaarden.
Laetitia verklaarde hoe zij als 14-jarige op straat door Dutroux in een busje werd ontvoerd en naar zijn huis gebracht. Hier werd ze door hem gedrogeerd en misbruikt. Ze zat samen met Sabine opgesloten in de kelderruimte. In tegenstelling tot Sabine geloofde Laetitia wel dat Dutroux onderdeel uitmaakte van een pedofielennetwerk. Het bestaan van dit netwerk werd niet onderzocht in het proces. Tussen 8 maart en 19 mei 2004 werden meer dan 560 getuigen gehoord. Na het requisitoir en de pleidooien kregen op 10 juni 2004 de verdachten het laatste woord. In een drie uur durend betoog presenteerde Dutroux zich andermaal als slachtoffer in plaats van dader.

 Arrest
Op 17 juni 2004 verklaarde de jury de verdachten schuldig aan alle ten laste gelegde feiten, behalve Michel Nihoul, die grotendeels werd vrijgesproken. Dutroux werd ook schuldig bevonden aan ontvoering van zes meisjes en moord op vier van hen. Volgens de jury stond hij aan het hoofd van een criminele bende en is hij ook verantwoordelijk voor de verkrachting van drie meisjes uit Slowakije. Op 22 juni 2004 werd hij veroordeeld tot levenslange opsluiting en 10 jaar terbeschikkingstelling van de regering. Dutroux vond het proces echter oneerlijk omdat van tevoren al vaststond dat hij veroordeeld zou worden en verklaarde in cassatie te willen gaan. Michelle Martin kreeg 30 jaar cel, Michel Lelièvre 25 jaar. Michel Nihoul werd vrijgesproken van betrokkenheid bij de ontvoeringen maar kreeg 5 jaar voor de drugshandel en bendevorming.

 Nasleep

 Parlementaire onderzoekscommissie
In de nasleep van het onderzoek werd een parlementaire onderzoekscommissie-Dutroux opgericht onder leiding van Marc Verwilghen.

Het rapport werd in april 1997 aangeboden. Behalve een analyse van de werking van de politie, beval de commissie aan de Gerechtelijke Politie bij de Parketten (GPP), de gemeentepolitie en de rijkswacht samen te voegen in één geïntegreerde politiedienst, gestructureerd op twee niveaus. De regering verwierp de suggestie en kwam in oktober 1997 met een eigen plan, waarbij ze niet koos voor een eenheidspolitie maar voor een politiestructuur met twee politiediensten. In het besluit kwam ook procureur des Konings Benoît Dejemeppe onder vuur, wiens ontslag werd gevraagd.

 Politiehervorming
Na het rapport van de commissie-Dutroux en het voorstel tot politiehervorming werd door de regering een eigen plan uitgewerkt, dat klaar was in oktober 1997. Daarbij werd niet gekozen voor een eenheidspolitie maar voor een politiestructuur met twee politiediensten.

Na de ontsnapping van Dutroux in april 1998 kwamen alle partijen met uitzondering van Vlaams Blok tot het Octopusakkoord. Dit akkoord, geconcretiseerd met de wet van 7 december 1998, creëerde een geïntegreerde politie, gestructureerd op twee niveaus. Het federale niveau bracht de voormalige centrale diensten van de rijkswacht en de voormalige Gerechtelijke Politie bij de Parketten samen. Het lokaal niveau verenigde de voormalige territoriale brigades van de rijkswacht en de voormalige korpsen van de gemeentepolitie.

 Strafuitvoering

Zowel Martin als Lelièvre hebben de voorwaardelijke invrijheidsstelling gevraagd, in toepassing van de Wet-Lejeune. Op 31 juli 2012 werd die toegekend, onder voorwaarden, voor Martin. Dit leidde tot verontwaardiging van de families van de slachtoffers en tot manifestaties. Op 19 augustus 2012 stapten 5000 mensen op naar het gerechtsgebouw, op initiatief van de vader van Julie Lejeune. Op 28 augustus 2012 verliet Michelle Martin de gevangenis.

 Grondwetsherziening
Ten gevolge van de zaak-Dutroux werd met de grondwetswijziging van 23 maart 2000 (BS 25 maart 2000) artikel 22bis ingevoegd in de Belgische grondwet, dat in hoofdzaak bepaalt dat elk kind recht heeft op de eerbiediging van zijn morele, lichamelijke, geestelijke en seksuele integriteit. Het betreft veeleer een symbolisch artikel.

 Statuut van het slachtoffer
De Wet van 12 maart 1998 voerde onder andere artikel 3bis in in de Voorafgaande Titel van het Wetboek van Strafvordering. De positie van slachtoffers is in zeer grote mate versterkt.

 Oprichting Hoge Raad voor Justitie
De Hoge Raad voor Justitie werd in 1999 opgericht ter objectivering van de benoeming van rechters.

 Oprichting Child Focus
Child Focus werd opgericht in 1998 door Jean-Denis Lejeune, de vader van Julie Lejeune.

 Chronologie
 26 april 1989 - Marc Dutroux wordt veroordeeld voor de verkrachting van vijf meisjes in 1985 en 1986 en krijgt een gevangenisstraf van 13 jaar.
 8 april 1992 - Dutroux komt dankzij toenmalig justitieminister Melchior Wathelet vervroegd vrij uit de gevangenis, hij zat 3 jaar van zijn straf uit.
 24 juni 1995 - De 8-jarige meisjes Julie Lejeune en Mélissa Russo worden ontvoerd in Luik.
 22 augustus 1995 - De 17-jarige An Marchal en de 19-jarige Eefje Lambrecks worden in Oostende gekidnapt.
 25 november 1995 - De 43-jarige Bernard Weinstein werd door Dutroux (vermoedelijk op deze datum) om het leven gebracht.
 13 december 1995 - Na tips van getuigen en de moeder van Dutroux doorzoekt opperwachtmeester René Michaux het huis van Dutroux in Marcinelle. Er worden kinderstemmen gehoord, maar Michaux denkt dat die van buiten komen.
 28 mei 1996 - De 12-jarige Sabine Dardenne wordt in het Waalse Kain ontvoerd.
 9 augustus 1996 - De 14-jarige Laetitia Delhez wordt in Bertrix ontvoerd.
 13 augustus 1996 - Dutroux, zijn vrouw Michelle Martin, en een vriend, Michel Lelièvre, worden gearresteerd op basis van getuigenverklaringen.
 15 augustus 1996 - De politie ontdekt Sabine Dardenne en Laetitia Delhez, die verborgen zaten in een cel in de kelder van Dutroux' huis.
 16 augustus 1996 - De politie arresteert Michel Nihoul op verdenking van samenzwering.
 17 augustus 1996 - De lichamen van Julie en Mélissa worden opgegraven in de tuin van een huis dat Dutroux bezit in Sars-la-Buissière. De meisjes zijn aan hongerdood gestorven. In dezelfde tuin wordt ook het lijk ontdekt van Bernard Weinstein, een Franse kompaan van Dutroux.
 18 augustus 1996 - Dutroux en Lelièvre bekennen de ontvoering van An en Eefje, maar ontkennen dat de tieners zijn vermoord.
 3 september 1996 - De politie vindt de lichamen van An en Eefje onder een schuurtje bij Weinsteins huis. Ze zijn levend begraven.
 21 september 1996 - Jean-Marc Connerotte, onderzoeksrechter in de zaak-Dutroux, trouwt met zijn vriendin met wie hij al 10 jaar samen is. Samen met hun zoontje bezoeken ze een benefietbijeenkomst voor de ouders van (de) verdwenen kinderen. Tijdens deze benefietbijeenkomst eten ze spaghetti. Connerotte zat samen met Michel Bourlet aan tafel, de procureur van Neufchâteau. Hij bleef slechts een uur aanwezig en sprak de aanwezige Sabine Dardenne niet. De magistraten kregen een vulpen van 27 euro elk, hun vrouwen een ruiker bloemen.
 15 oktober 1996 - Het spaghetti-arrest: het Hof van Cassatie haalt onderzoeksrechter Jean-Marc Connerotte van de zaak omdat het bijwonen van deze benefietbijeenkomst waar hij twee geschenken in ontvangst nam (het bord spaghetti en een vulpen) het eerlijk verlopen van het proces in het gedrang brengen.
 20 oktober 1996 - De Witte Mars. Zo'n 300.000 mensen demonstreren in Brussel om hun verontwaardiging over de vertragingen en fouten in het onderzoek naar Dutroux te ventileren.
 24 oktober 1996 - Uit vrees dat het Dutroux-onderzoek wordt verknoeid, roept het Belgisch parlement een onafhankelijke onderzoekscommissie in het leven om de Zaak Dutroux te onderzoeken, evenals de mogelijke procedurefouten bij de Belgische politie en justitie. Voorzitter wordt Marc Verwilghen.
 15 maart 1997 - De commissie-Dutroux levert vernietigende kritiek op de politie en het Ministerie van Justitie, die een puinhoop maakten van de onderzoeken naar de verdwenen meisjes.
 6 mei 1997 - De commissie-Dutroux gaat opnieuw aan het werk en onderzoekt of Dutroux door hooggeplaatste figuren werd beschermd.
 15 februari 1998 - In het tweede rapport van de commissie staat dat de bende van Dutroux geen bescherming van hogerhand genoot, maar wel profiteerde van corruptie, slordigheid en professionele onbekwaamheid.
 23 april 1998 - Dutroux ontsnapt aan zijn bewakers in het gerechtsgebouw van Neufchâteau, maar wordt vier uur later weer opgepakt in Herbeumont Saint-Médard door boswachter Stéphane Michaux. Minister van Binnenlandse Zaken Johan Vande Lanotte en minister van Justitie Stefaan De Clerck bieden diezelfde dag nog hun ontslag aan en worden opgevolgd door respectievelijk Louis Tobback en Tony Van Parys. Ook het hoofd van de rijkswacht, Willy Deridder, neemt ontslag.
 14 juli 1999 - Hubert Massa, advocaat-generaal belast met het dossier-Dutroux, pleegt zelfmoord.
 15 december 1999 - Michel Nihoul wordt voorwaardelijk vrijgelaten bij gebrek aan bewijzen.
 15 maart 2002 - Onderzoeksrechter Jacques Langlois voltooit het onderzoek naar Dutroux.
 17 januari 2003 - De Raadkamer in Neufchâteau beslist Dutroux, Martin en Lelièvre voor het Hof van Assisen te brengen. Nihoul wordt buiten vervolging gesteld. Procureur des Konings Bourlet en enkele burgerlijke partijen tekenen beroep aan.
 30 april 2003 - De Luikse Kamer van Inbeschuldigingstelling (KI) volgt procureur Bourlet en verwijst ook Nihoul naar het Hof van Assisen.Nihoul naar assisen, www.standaard.be, 1 mei 2003
 8 december 2003 - Procureur Bourlet legt de 27 pagina's lange akte van beschuldiging neer.
 1 maart 2004 - Het proces-Dutroux begint in Aarlen.
 14 juni 2004 - Na 56 procesdagen trekken de twaalf juryleden zich terug, om zich te buigen over de schuld of onschuld van de verdachten.
 17 juni 2004 - Dutroux wordt onder meer schuldig bevonden aan verschillende moorden.
 22 juni 2004 - Dutroux wordt veroordeeld tot levenslange opsluiting en 10 jaar terbeschikkingstelling van de regering. Michelle Martin krijgt 30 jaar cel, Michel Lelièvre 25 jaar en Michel Nihoul 5 jaar. Dutroux gaat in cassatie.
 16 december 2004 - Het Hof van Cassatie besluit dat er geen procedurefouten gemaakt zijn. De straffen blijven gelden.
 oktober 2005 - Lelièvre vraagt een eerste keer om voorwaardelijk in vrijheid gesteld te worden. Dat wordt geweigerd omdat hij zijn slachtoffers nog niet heeft vergoed.
 2007 - De Belgische staat wordt door het Europees Hof voor de Rechten van de Mens veroordeeld tot het betalen van 6.000 euro schadevergoeding aan Lelièvre, omdat zijn voorlopige hechtenis onredelijk lang had geduurd. Lelièvre zat, net als Marc Dutroux en Michelle Martin, al bijna acht jaar in de cel toen hij in 2004 werd veroordeeld. Het geld gaat naar zijn slachtoffers.
 april 2007 - Michelle Martin dient een aanvraag in tot voorwaardelijke invrijheidstelling, in toepassing van de Wet-Lejeune. Dit wordt verworpen gelet op de ernst van de feiten, het gebrek aan reklasseringsvooruitzicht en de risico's verbonden aan het psychologisch profiel van de veroordeelde.
 oktober 2008 - Martin dient een tweede aanvraag in, die wordt verworpen.
 november 2009 - Martin dient een derde aanvraag in, die opnieuw wordt verworpen.
 8 mei 2011 - Martin verkrijgt, na de helft van haar straf te hebben uitgezeten, voorwaardelijke invrijheidstelling. Half juni 2011 zijn de hieraan verbonden voorwaarden niet vervuld, en Martin wordt niet voorwaardelijk in vrijheid gesteld.
 april 2012 - Dutroux vraagt penitentiair verlof, waarbij hij elke maand een dag en een nacht buiten de gevangenis zou mogen verblijven (dit kan ten vroegste een jaar voor hij een derde van zijn straf heeft uitgezeten). De gevangenisdirectie wijst af.
 31 juli 2012 - De strafuitvoeringsrechtbank beslist opnieuw Michelle Martin voorwaardelijk in vrijheid te stellen. Het klooster van de Arme Klaren in Malonne is bereid haar op te vangen. Het Openbaar Ministerie tekent echter cassatieberoep aan. De voorwaardelijke vrijlating leidt tot protesten.
 19 augustus 2012 - De families van Julie Lejeune en An Marchal, samen met Laetitia Delhez, organiseren een manifestatie tegen de voorwaardelijke invrijheidstelling van Martin. Er zijn 5000 deelnemers. Na de manifestatie worden ze ontvangen door minister van justitie Annemie Turtelboom en minister van binnenlandse zaken Joëlle Milquet, een week later door premier Elio Di Rupo.
 28 augustus 2012 - Het Hof van Cassatie doet uitspraak dat ze geen procedurefouten heeft gevonden bij de beslissing van de strafuitvoeringsrechtbank. Enkele uren later verlaat Martin de gevangenis op weg naar het klooster in Malonne.Michelle Martin is aangekomen in Malonne, www.deredactie.be, 28 augustus 2012
 6 september 2012 - De regeringstop concretiseert, naar aanleiding van de protesten tegen de vrijlating van Martin, het regeerakkoord waarin een gevoelige aanscherping van de voorwaardelijke invrijheidstelling was opgenomen.
 13 september 2012 - Dutroux vraagt invrijheidsstelling met enkelband aan (dit kan vanaf zes maanden vóór de eerste verschijning voor de strafuitvoeringsrechtbank). Volgens Ronny Baudewijn, de advocaat van Dutroux, hoopt deze ook ooit echt vrij te komen. Hij verklaart urenlang met hem gediscussieerd te hebben over berouw en spijt, wat Dutroux echter niet heeft: Hij vindt het wel spijtig dat er mensen gestorven zijn, maar hij voelt zich niet schuldig. Als psychopaat kan hij zich niet inleven in wat hij anderen aandoet, hij ziet enkel waar hij recht op heeft.
 april 2013 - Dutroux zal één derde van zijn straf uitgezeten hebben en zal voor de eerste keer door de strafuitvoeringsrechtbank opgeroepen worden (ook als hij zelf niet het initiatief neemt met een vraag voor een voorwaardelijke invrijheidsstelling).
3 december 2019 - Michel Lelièvre wordt na 15 jaar cel (van de 17) vrijgelaten. Daarna gebeurde de Zwarte Mars, het tegenovergestelde van de Witte Mars.

 Afbeeldingen

Bibliografie
 Michel Bouffioux, Ce n'est pas terminé!, uitgeverij Luc Pire, 1995, , 343p.
 Door Hilde Heppe vertaald onder de titel Het is niet gedaan! Een gevecht voor Julie en Mélissa, uitgeverij EPO, 1998,
 Wim Winckelmans, De Commissie-Dutroux. Het rapport (met commentaar), 1997,
 Hans Knoop, De zaak Marc Dutroux, 1998,
 Annemie Bulté, Douglas De Coninck en Marie-Jeanne Van Heeswyck, De X dossiers - Wat België niet mocht weten over de zaak-Dutroux, 1999,
 Victor Dutroux, Mijn zoon Marc Dutroux, 2003,
 Michel Bouffioux, Marie-Jeanne Van Heeswyck, Dutroux et consorts - La face cachée de l'enquête, uitgeverij Michel Lafon, 1 maart 2004,  EAN 9782749901312, 350p.
 Sabine Dardenne (voorlaatste slachtoffer van Dutroux), Ik was twaalf en ik fietste naar school'', 2005,

Misdrijf in 1996
Dutroux
Seksueel geweld
Geschiedenis van België in de 20e eeuw
Geschiedenis van Luxemburg (provincie)
Dutroux
Marc Dutroux


Technical Abstract: Current technologies for next generation sequencing (NGS) have revolutionized metagenomics analysis of clinical samples. One advantage of the NGS platform is the possibility to sequence the genetic material in samples without any prior knowledge of the sequence contained within. Sequence-Independent, Single-Primer Amplification (SISPA) is a primer initiated technique to achieve the non-selective amplification of heterogeneous populations. SISPA is especially useful when the nucleotide sequence of the desired molecule is both unknown and present in limited amounts making its recovery by standard procedures technically difficult. We have modified the SISPA methodology to genome sequencing of RNA viruses. The utility of the method on various types and sources of RNA viruses, obtaining complete genome sequence of avian influenza virus (AIV), Newcastle disease virus (NDV), infections bronchitis virus (IBV) was shown in this study. The detection limit depended on the viral load in the samples. Our results demonstrate complete or near complete virus genome identification with titers at or above 104.5 EID50/ml (50% embryo infectious dose), and virus detection with titers at or above 103 EID50/ml. The application of SISPA - NGS will be discussed, together with its utility for whole genome sequencing of RNA viruses, metagenomics analysis of clinical samples and recovery of low abundance genetic sequences illustrated with AIV, NDV and IBV.


text:
#import "ResourceManagerOutlineHandler.h"
#import "ImageAndTextCell.h"
#import "ResourceManager.h"
#import "ResourceManagerUtil.h"
#import "CocosBuilderAppDelegate.h"
#import "CCBGlobals.h"

@implementation ResourceManagerOutlineHandler

@synthesize resType;

- (void) reload
{
    [resourceList reloadData];
}

- (id) initWithOutlineView:(NSOutlineView *)outlineView resType:(int)rt
{
    return [self initWithOutlineView:outlineView resType:rt imagePreview:NULL lblNoPreview:NULL];
}

- (id) initWithOutlineView:(NSOutlineView*)outlineView resType:(int)rt imagePreview:(NSImageView*)preview lblNoPreview:(NSTextField*)lbl
{
    self = [super init];
    if (!self) return NULL;

    resManager = [ResourceManager sharedManager];
    [resManager addResourceObserver:self];

    resourceList = [outlineView retain];
    imagePreview = [preview retain];
    lblNoPreview = [lbl retain];
    resType = rt;

    ImageAndTextCell* imageTextCell = [[[ImageAndTextCell alloc] init] autorelease];
    [[resourceList outlineTableColumn] setDataCell:imageTextCell];
    [[resourceList outlineTableColumn] setEditable:YES];

    [resourceList setDataSource:self];
    [resourceList setDelegate:self];
    [resourceList setTarget:self];
    [resourceList setDoubleAction:@selector(doubleClicked:)];

    return self;
}

- (NSInteger)outlineView:(NSOutlineView *)outlineView numberOfChildrenOfItem:(id)item
{
    // Do not display directories if only one directory is used
    if (item == NULL && [resManager.activeDirectories count] == 1)
    {
        item = [resManager.activeDirectories objectAtIndex:0];
    }

    // Handle base nodes
    if (item == NULL)
    {
        return [resManager.activeDirectories count];
    }

    // Fetch the data object of directory resources and use it as the item object
    if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
        if (res.type == kCCBResTypeDirectory)
        {
            item = res.data;
        }
    }

    // Handle different nodes
    if ([item isKindOfClass:[RMDirectory class]])
    {
        RMDirectory* dir = item;

        NSLog(@"resourcesForType: %d",resType);

        NSArray* children = [dir resourcesForType:resType];
        return [children count];
    }
    else if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
        if (res.type == kCCBResTypeSpriteSheet)
        {
            NSArray* frames = res.data;
            return [frames count];
        }
        else if (res.type == kCCBResTypeAnimation)
        {
            NSArray* anims = res.data;
            return [anims count];
        }
    }

    return 0;
}

- (id)outlineView:(NSOutlineView *)outlineView child:(NSInteger)index ofItem:(id)item
{
    // Do not display directories if only one directory is used
    if (item == NULL && [resManager.activeDirectories count] == 1)
    {
        item = [resManager.activeDirectories objectAtIndex:0];
    }

    // Return base nodes
    if (item == NULL)
    {
        return [resManager.activeDirectories objectAtIndex:index];
    }

    // Fetch the data object of directory resources and use it as the item object
    if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
        if (res.type == kCCBResTypeDirectory)
        {
            item = res.data;
        }
    }

    // Return children for different nodes
    if ([item isKindOfClass:[RMDirectory class]])
    {
        RMDirectory* dir = item;
        NSArray* children = [dir resourcesForType:resType];
        return [children objectAtIndex:index];
    }
    else if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
        if (res.type == kCCBResTypeSpriteSheet)
        {
            NSArray* frames = res.data;
            return [frames objectAtIndex:index];
        }
        else if (res.type == kCCBResTypeAnimation)
        {
            NSArray* anims = res.data;
            return [anims objectAtIndex:index];
        }
    }

    return NULL;
}

- (BOOL)outlineView:(NSOutlineView *)outlineView isItemExpandable:(id)item
{
    // Do not display directories if only one directory is used
    if (item == NULL && [resManager.activeDirectories count] == 1)
    {
        item = [resManager.activeDirectories objectAtIndex:0];
    }

    if ([item isKindOfClass:[RMDirectory class]])
    {
        return YES;
    }
    else if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
        if (res.type == kCCBResTypeSpriteSheet) return YES;
        else if (res.type == kCCBResTypeAnimation) return YES;
        else if (res.type == kCCBResTypeDirectory) return YES;
    }

    return NO;
}

- (id)outlineView:(NSOutlineView *)outlineView objectValueForTableColumn:(NSTableColumn *)tableColumn byItem:(id)item
{
    if ([item isKindOfClass:[RMDirectory class]])
    {
        RMDirectory* dir = item;
        return [dir.dirPath lastPathComponent];
    }
    else if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
        return [res.filePath lastPathComponent];
    }
    else if ([item isKindOfClass:[RMSpriteFrame class]])
    {
        RMSpriteFrame* sf = item;
        return sf.spriteFrameName;
    }
    else if ([item isKindOfClass:[RMAnimation class]])
    {
        RMAnimation* anim = item;
        return anim.animationName;
    }
    return @"";
}

- (void) outlineView:(NSOutlineView *)outlineView setObjectValue:(id)object forTableColumn:(NSTableColumn *)tableColumn byItem:(id)item
{
    NSLog(@"Value: %@", object);
}

- (NSImage*) smallIconForFile:(NSString*)file
{
    NSImage* icon = [[NSWorkspace sharedWorkspace] iconForFile:file];
    [icon setScalesWhenResized:YES];
    icon.size = NSMakeSize(16, 16);
    return icon;
}

- (NSImage*) smallIconForFileType:(NSString*)type
{
    NSImage* icon = [[NSWorkspace sharedWorkspace] iconForFileType:type];
    [icon setScalesWhenResized:YES];
    icon.size = NSMakeSize(16, 16);
    return icon;
}

- (void)outlineView:(NSOutlineView *)outlineView willDisplayCell:(id)cell forTableColumn:(NSTableColumn *)tableColumn item:(id)item
{
    NSImage* icon = NULL;

    if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = item;
#warning Do all images by type
        if (res.type == kCCBResTypeImage)
        {
            icon = [self smallIconForFileType:@"png"];
        }
        else
        {
            if (res.type == kCCBResTypeDirectory)
            {
                RMDirectory* dir = res.data;
                if (dir.isDynamicSpriteSheet)
                {
                    icon = [NSImage imageNamed:@"reshandler-spritesheet-folder.png"];
                }
                else
                {
                    icon = [self smallIconForFile:res.filePath];
                }
            }
            else
            {
                icon = [self smallIconForFile:res.filePath];
            }
        }
    }
    else if ([item isKindOfClass:[RMSpriteFrame class]])
    {
        icon = [self smallIconForFileType:@"png"];
    }
    else if ([item isKindOfClass:[RMAnimation class]])
    {
        icon = [self smallIconForFileType:@"p12"];
    }
    [cell setImage:icon];
}

- (BOOL) outlineView:(NSOutlineView *)outlineView writeItems:(NSArray *)items toPasteboard:(NSPasteboard *)pasteboard
{
    NSString* spriteFile = NULL;
    NSString* spriteSheetFile = NULL;
    NSString* ccbFile = NULL;
    NSString* audioFile = NULL;

    for (id item in items)
    {
        if ([item isKindOfClass:[RMResource class]])
        {
            RMResource* res = item;
            if (res.type == kCCBResTypeImage)
            {
                spriteFile = [ResourceManagerUtil relativePathFromAbsolutePath: res.filePath];
            }
            else if (res.type == kCCBResTypeCCBFile)
            {
                ccbFile = [ResourceManagerUtil relativePathFromAbsolutePath: res.filePath];
            }
            else if (res.type == kCCBResTypeAudio)
            {
                audioFile = [ResourceManagerUtil relativePathFromAbsolutePath: res.filePath];
            }
        }
        else if ([item isKindOfClass:[RMSpriteFrame class]])
        {
            RMSpriteFrame* frame = item;
            spriteFile = frame.spriteFrameName;
            spriteSheetFile = [ResourceManagerUtil relativePathFromAbsolutePath: frame.spriteSheetFile];
            if (!spriteSheetFile) spriteFile = NULL;
        }
    }

    if (spriteFile)
    {
        NSMutableDictionary* clipDict = [NSMutableDictionary dictionary];
        [clipDict setObject:spriteFile forKey:@"spriteFile"];
        if (spriteSheetFile)
        {
            [clipDict setObject:spriteSheetFile forKey:@"spriteSheetFile"];
        }

        NSData* clipData = [NSKeyedArchiver archivedDataWithRootObject:clipDict];
        [pasteboard declareTypes:[NSArray arrayWithObject:@"com.cocosbuilder.texture"] owner:NULL];
        [pasteboard setData:clipData forType:@"com.cocosbuilder.texture"];

        return YES;
    }
    else if (ccbFile)
    {
        NSMutableDictionary* clipDict = [NSMutableDictionary dictionary];
        [clipDict setObject:ccbFile forKey:@"ccbFile"];

        NSData* clipData = [NSKeyedArchiver archivedDataWithRootObject:clipDict];
        [pasteboard declareTypes:[NSArray arrayWithObject:@"com.cocosbuilder.ccb"] owner:NULL];
        [pasteboard setData:clipData forType:@"com.cocosbuilder.ccb"];

        return YES;
    }
    else if (audioFile)
    {
        NSMutableDictionary* clipDict = [NSMutableDictionary dictionary];
        [clipDict setObject:audioFile forKey:@"audioFile"];

        NSData* clipData = [NSKeyedArchiver archivedDataWithRootObject:clipDict];
        [pasteboard declareTypes:[NSArray arrayWithObject:@"com.cocosbuilder.audio"] owner:NULL];
        [pasteboard setData:clipData forType:@"com.cocosbuilder.audio"];

        return YES;
    }

    return NO;
}

- (void) outlineViewSelectionDidChange:(NSNotification *)notification
{
    id selection = [resourceList itemAtRow:[resourceList selectedRow]];

    NSImage* preview = NULL;
    if ([selection respondsToSelector:@selector(preview)])
    {
        preview = [selection preview];
    }

    [imagePreview setImage:preview];

    if (preview) [lblNoPreview setHidden:YES];
    else [lblNoPreview setHidden:NO];

#warning Hackish solution to make multiple selections look good
    NSLog(@"needsDisplay!");
    [resourceList setNeedsDisplay];
}

- (void) doubleClicked:(id)sender
{
    id item = [resourceList itemAtRow:[resourceList clickedRow]];

    if ([item isKindOfClass:[RMResource class]])
    {
        RMResource* res = (RMResource*) item;
        if (res.type == kCCBResTypeCCBFile)
        {
            [[CocosBuilderAppDelegate appDelegate] openFile: res.filePath];
        }
        else if (res.type == kCCBResTypeJS || res.type == kCCBResTypeJSON)
        {
            [[CocosBuilderAppDelegate appDelegate] openJSFile:res.filePath];
        }
    }

}

- (BOOL) outlineView:(NSOutlineView *)outlineView shouldEditTableColumn:(NSTableColumn *)tableColumn item:(id)item
{
    NSLog(@"shouldEdit (ResManager)");
    return YES;
}

- (void) resourceListUpdated
{
    [resourceList reloadData];
}

- (void) setResType:(int)rt
{
    resType = rt;
    [resourceList reloadData];
}

- (void) dealloc
{
    [resourceList release];
    [imagePreview release];
    [lblNoPreview release];
    [super dealloc];
}

@end

redpajama_set_name: RedPajamaGithub


I am back in Santa Monica after my vacation, and as I write this, on Sunday afternoon, I am still savoring the lox and bagels I ate this morning. When you fly back from Europe straight to the west coast you tend to wake up early the next day. This morning, about six, I realized that the thing for me to do was to drive to Manhattan Bagel and satisfy my urge for a breakfast I couldn't get in Italy.
I need to travel, but wandering is something else. Travel may broaden the mind, I certainly think so, but more so if you have a home to come back to.
I am, however, one of the species "Indefatigibus Berlitzus," one of those perverse optimists who keeps trying to learn a foreign language, in my case Italian, indefinitely even though the results are always the same -- negligible.
I started 20 years ago, first with a private teacher, then with Berlitz tapes. When I got married, my wife joined my obsession and we I took classes at Santa Monica College. Then more self study. Recently I found a website, cyberitalian.com, and I have been studying on-line.
But still it's the same. I can usually make myself understood in Italian, but I am hopeless at understanding what anyone says, particularly if we are trying to have a real conversation.
This past week, after spending two weeks with my family in their Umbrian village, and after my wife returned to California to attend a conference, my son and I traveled to northern Italy to see two sets of Italian friends. Years ago my wife and I met both families under typical travel circumstances.
We met Marco, who lives near Turin with his wife Cia and three sons, on an flight from Italy to L.A. To brush up on his English, Marco was reading "Charlotte's Web," and that lead to a conversation.
We met other friends, Mariagrazia and Mauro, who live near Milan, on our honeymoon. They happened to be on theirs, too, and somehow two couples in a pizzeria on Capri recognized a postnuptial bound, and we started to talk.
Over the years, the two couples have become quite good friends of ours. We don't see them often, but both couples have boys not too much older than our Henry. We have stayed in touch, and we try to see each other when we can.
This year Henry and I met Marco and Cia and two of their boys for a few days of hiking in the Dolomites, and then we flew back by way of Milan so that we could spend a couple days with Mariagrazia and Mauro and their son, who likes to ride his motor bike and fly model airplanes by remote control.
Without getting too sentimental, these friendships are important to us, we hope they are similarly important to our friends, and it's worth reflecting that these friendships would not exist but for the fact that all four of the other adults learned to speak a foreign language, namely English.
My wife and I have advanced degrees, but neither of us managed to acquire, in all our years in the American educational system, the working grasp of a foreign language.
Our friends' children are learning foreign languages, as you might expect. Not that it's easy for them. They have to work at it. There's an expectation that Europeans fall naturally into multi-lingualism -- perhaps because they start learning languages in elementary school or because of proximity to other countries, but in my experience that is not the case. Very few Italians speak English despite the fact that they start learning it early in school.
Interestingly, when I talked to my friends about how their boys learned languages, they all discounted what the kids learn in elementary school. They characterized foreign language instruction in elementary school as mere "games," by which the kids learned not much beyond colors and how to count.
But starting in middle school, the kids work hard at learning languages. For instance, Mauro's and Mariagrazia's boy took three years of French in middle school and then switched to English in high school.
Marco's and Cia's boys had an advantage because they lived for awhile in the U.S. while Marco was doing research, and they learned basic English by attending American schools, but to solidify their knowledge of the language their parents had the boys each attend the American school in Turin for at least a few years.
But to show how serious Italians can take languages (and, for that matter, learning in general), their boys have attended the local "liceo classico," a public high school in which all the students take a modern language in addition to Latin and ancient Greek. Each year.
The reasons to learn a foreign language go beyond the ability to make international friendships, and in a multi-lingual city like Los Angeles, a city that lives on international commerce, the value of languages should be obvious. Languages are windows into other cultures.
But learning a language also provides the learner with a rigorous framework, like mathematics or music, that is helpful in other fields. Languages engage the brain.
American schools have never given languages a high priority. Except for the bilingual immersion program that starts at Edison Elementary, and an optional, nine-week "exploratory" session available in seventh grade, public schools in Santa Monica and Malibu start foreign language instruction in eighth grade. That's the same as when I was in school 40 years ago, before the "global economy" and before the opening up of immigration quotas.
While elementary school children may not have the intellectual maturity to learn a second language in a classroom, as opposed to by immersion, there is no reason to believe that American sixth graders -- like their counterparts in Italy -- could not do so. And like their counterparts around the world, they will still have time during the day for their other subjects.
Consider the extremely successful music programs at our local schools. Sixth graders learn how to play instruments, read music, and understand more than the rudiments of music theory, in an environment that is both intellectually rigorous and inclusive.
In the context of the latest schools budget crisis, it may seem like dreaming to talk about how schools should not be merely good, but better, but it's time for the schools to start thinking of teaching a second language -- Spanish comes to mind -- beginning in sixth grade.


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TV Review: Grease Live!
By Olympus Athens | @ | January 31st, 2016 at 11:06 pm
Based on the 1971 Musical & 1978 Film "Grease"
Directed by Alex Rudzinski
Written Robert Cary & Jonathan Tolins
Starring Julianne Hough, Aaron Tveit, Vanessa Hudgens, Keke Palmer, Carlos Pena Vega, Carly Rae Jepsen, Kether Donohue, David Del Rio, Jordan Fisher, Andrew Call.
Air Date: Sunday, January 31st, 2016, 7:00pm
Grease was the word tonight as Grease Live! hit television screens from 7:00-10:00pm ET on FOX. Live shows are all the rage nowadays, trending the instant they are on. This version combines both the musical and film version from the 70s. We know the story (and songs) by heart – good girl Sandy and greaser Danny Zuko have a summer beach romance. But romance goes awry when they "accidentally" run into each other at the same school. Danny has a rep to protect, and Sandy is shy and a goody-two shoes. But somehow, by meeting somewhere in the middle, they realize they "go together."
Spoilers below.
Topics: News, Recaps, Reviews, Television, TV Reviews
Tags: Aaron Tveit, Alex Rudzinski, Ana Gasteyer, Andrew Call, Boyz II Men, Carlos Pena Vega, Carly Rae Jepsen, David Del Rio, Eve Plumb, Fox, Grease, Grease Live!, Jessie J, Joe Jonas, Jonathan Tolins, Jordan Fisher, Julianne Hough, Keke Palmer, Kether Donohue, Mario Lopez, Noah Robbins, Robert Cary, Vanessa Hudgens, Yvette Gonzalez-Nacer
'Grease' "You're the One That I Want" Hair Metal Style Cover (Video)
By Olympus Athens | @ | March 5th, 2015 at 9:00 am
Lots of times, the stuff on one's newsfeed doesn't warrant a second (or even a first) glance. But sometimes scrolling pays off and you thank whatever gods or nothing you believe in that you have really cool Facebook friends that find awesome shit.
Allow me to share this awesome shit…. Please watch the videos here below. You will thank me. You may even want to give me an award or something for sharing.
A band named Tragedy: All Metal Tribute to the Bee Gees & Beyond (Squeee!!) has covered "You're the One That I Want" from the 1978 iconic movie musical, Grease, first sung by pre-weird John Travolta and Olivia Newton-John. THAT was a good song accompanied by a good scene. What Tragedy does far outperforms the original and I LOVE the original to this day.
Topics: Because Awesome, Music, News, Videos
Tags: Grease, Hair Metal, The Bee Gees, Tragedy: All Metal Tribute to the Bee Gees & Beyond
Grease Celebrates Its 35th Anniversary!
By Stoogeypedia | June 16th, 2013 at 10:00 am
Grease, one of the great, most loved, and successful musical film adaptations of all time, celebrates its 35 anniversary today.
Brimming with memorable set pieces, song numbers, consummate dancing, a smart script, and of course, the lead performance by John Travolta, fresh off his superstar status in Saturday Night Fever and arguably elevating that star status even to a higher plane with the success of this film, Grease still remains a benchmark in cinema, a rare striking an iron red hot of a meshing of casting, production, and creation. It's pretty much ingrained in the American fabric in this current age we live in, and even if there is a slight polarization regarding the film, there's no denying its power. Like Saturday Night Fever, Grease remains almost like two films which are recognized by the viewing public: the pushing the envelope original PG version which has some mild but albeit adult themes in it, and the watered down, readily accessible for the ABC Family, Disney Channel, VH1 Classic mindset and demographic and thus, the real intention of many of its characters are slightly askew and the original story remains in a slight flux. But regardless of that, it's still the feel good charm and energy that Grease radiates which made it a success in the cinema and beyond, on the lighted stages of live productions, which now transcend to being performed around the world.
Topics: Features, Movies, Music
Tags: Grease, Jeff Conaway, John Travolta, Olivia Newton-John
Happy 59th Birthday To John Travolta
By Stoogeypedia | February 18th, 2013 at 11:04 am
Happy 59th birthday today to John Travolta, the consummate, versatile actor, who rose from rather humble beginnings in the 1970s to become first a teen heartthrob, then a superstar dancer, singer, and handsome man-about-town soaking up every ounce of the Hollywood limelight. The man has weathered many ups and downs career-wise, going to almost unabashed obscurity in the mid 1980s, and then finally rising to the A-list once again when he co-starred in Quentin Tarantino's love letter to low life, Pulp Fiction. Travolta remains a viable, bankable actor to this very day, and a symbol of contemporary movie musicals and a measuring stick for pop cultural figures of the 1970s.
The career of Travolta spans eras and generations, the earliest of which were ones who discovered him on the ABC-TV sitcom Welcome Back Kotter. On that show, he played Vinnie Barbarino, who was one of the "Sweathogs," a juvenile group of underachievers in a Brooklyn High School who parlayed their styles and attitudes more like the Marx Brothers than the rough and tumble dangerous teenagers that kids of that stripe in reality really would be. Harmless and gregarious at every turn on the show, the Sweathogs were really just a comprised second banana ensemble to the show's main star, Gabe Kaplan, who played their teacher Gabe Kotter and who, since he himself had been a Sweathog at one time, acted as a mentor and lighthearted and always trusting and caring foil to their comic absurdities. Travolta quickly stood out from the ensemble cast, with his perfectly blow-dried hairstyle, easy on the eyes good looks, an irresistible silly charm, and especially his oft-repeated use of the catchphrase which became synonymous with the program, "Up Your Nose With A Rubber Hose." The show was relatively popular during the mid 1970s and some key marketing of the program (games, lunchboxes, and T-shirts) kept Travolta's visage and image on teenager's minds across the United States.
Topics: Features, Movies
Tags: Grease, John Travolta, Saturday Night Fever
Paramount's Rose Parade Float Celebrates 'Star Trek', 'Transformers,' 'Grease'
By Empress Eve | @ | January 2nd, 2012 at 6:34 pm
Paramount Pictures participated today in the 123rd Rose Parade in California with a float celebrating some of their most memorable franchises, like Star Trek, Transformers, and Grease.
The 55-foot-long float, called "Paramount Pictures … 100 Years Of Movie Magic," marked Paramount's first time in the annual parade and contained replicas of Star Trek's famed starship, the USS Enterprise; the Autobot Bumblebee from Transformers; and Greased Lightning, the car from Grease, as well as other symbols of Paramount's past.
Topics: Movies, News, Videos
Tags: George Takei, Grease, Paramount, Paramount Pictures, Rose Parade, Star Trek, Transformers
'Babylon 5' Actor Jeff Conaway Dies At Age 60
By cGt2099 | May 28th, 2011 at 11:58 am
Actor Jeff Conaway passed away yesterday, May 27, 2011, at the age of 60. Geek fans will remember him from television shows such as Babylon 5 and Freddy's Nightmares, but he is also more popularly known from Grease and Taxi.
Conaway's passing is a sad long story… At the beginning of May he was apparently dealing with pneumonia, and was taking a lot of medication to deal with the illness. Several days later, he was found unconscious on May 11, where it was discovered he had overdosed on painkillers (some media outlets have speculated other prescription medications as well) almost 10 hours before being found.
He was placed in a medically induced coma in the hospital, and was subsequently taken off life support on May 26. The following day, he died.
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Topics: Movies, News, Obit, Television
Tags: Babylon 5, Freddy's Nightmares, Grease, Jeff Conaway, Murder She Wrote, Taxi, The Bold and The Beautiful
DVD Review: Grease (Blu-ray)
By WordSlinger | May 23rd, 2009 at 10:48 pm
Rockin' Rydell Blu-ray Edition
Directed by Randal Kleiser
Starring John Travolta, Olivia Newton-John, Stockard Channing, Jeff Conaway
It's hard to imagine there's anybody out there who has not seen this landmark piece of American cinema. Forget Troy and Gabriella, they've got nothing on Danny (John Travolta) and Sandy (Olivia Newton-John) and Grease will always be the original high school musical. Even 31 years after its original release, Grease is still regarded as the definitive American musical and a masterpiece of a film.
The Blu-ray release, however, is not as ground-breaking as the film itself. Though long-time fans of the film may jump at the chance for a high-def version, if they already own the DVD "Rockin' Rydell" edition, there is little reason to repurchase.
Even as Blu-ray technology becomes more widespread, it seems a vast majority of people who use it are videophiles who want the absolute best. Unfortunately, the picture quality on the Grease Blu-ray leaves a bit to be desired. The disc contains a 1080p high-def transfer of the film, but seems spotty at points. Though the film's vibrant colors really pop in high definition, many scenes lack the crispness one has come to expect from Blu-ray. This is especially noticeable when skipping chapters, as one scene may look great but the next looks practically blurry by comparison.
Topics: Blu-ray, DVD Reviews, DVDs, Movies, Reviews
Tags: Grease, Jeff Conaway, John Travolta, Olivia Newton-John, Randal Kleiser, Stockard Channing

redpajama_set_name: RedPajamaCommonCrawl


Here's the stuff dreams are made of: chocolate almond sugar. Scroll down for the guilt-free good stuff.
Place the almonds in a tray with the oil. Place in the oven for 10 minutes.
Add the chocolate to a bowl (or blender) and melt in the microwave for 1 minute.
Add the roasted nuts to the blending mug / food processor and blitz.
It might take a few goes before you get the smooth, buttery consistency you want. I scraped down the sides after blitzing the mixture twice.
Once blitzed, this yields a smooth, slightly grainy, chocolate sauce or call it chocolate almond butter.
It makes a perfect dip for Apple slices, a protein-packed teaspoon that can be added to smoothies, or a healthier alternative to Nutella.
It keeps well in the fridge as long as it's stored in an airtight jar.


Indestructibone is a virtually indestructible dog bone. It is made especially for those dogs that are tough on their chew toys. It has a small treat hole on each end so that you can add your dog's favourite treat.
Indestructibone Original is made for dogs between 13-23kg.
This product comes with a 90 day – 1 time replacement guarantee.
This Indestructibone weighs approximately 0.2kg.