Seven Novel Variants of Weiss-Kruszka Syndrome and Phenotype Expansion.

Weiss-Kruszka syndrome (WKS) is a rare genetic disorder characterized by metopic ridging, ptosis, arched eyebrows, down slanting palpebral fissures, abnormalities in the corpus callosum, cardiac malformations, and variable neurodevelopmental delay. To date, 32 individuals with a diagnosis of WKS have been reported in the literature. The syndrome is caused by a heterozygous pathogenic variant in the ZNF462 gene or a deletion of the 9p31.2 region involving ZNF462. There is significant phenotypic heterogeneity and intrafamilial variability among these patients. Our study reviewed nine patients from seven unrelated families and identified seven novel heterozygous ZNF462 variants through exome sequencing. GestaltMatcher analysis of our cohort's facial images, alongside previously published images of ZNF462 patients, demonstrated a high degree of facial similarity. Further longitudinal research is needed to delineate this rare condition's long-term health implications and adult-onset features.

Human Genetics of Atrial Septal Defect.

Although atrial septal defects (ASD) can be subdivided based on their anatomical location, an essential aspect of human genetics and genetic counseling is distinguishing between isolated and familiar cases without extracardiac features and syndromic cases with the co-occurrence of extracardiac abnormalities, such as developmental delay. Isolated or familial cases tend to show genetic alterations in genes related to important cardiac transcription factors and genes encoding for sarcomeric proteins. By contrast, the spectrum of genes with genetic alterations observed in syndromic cases is diverse. Currently, it points to different pathways and gene networks relevant to the dysregulation of cardiomyogenesis and ASD pathogenesis. Therefore, this chapter reflects the current knowledge and highlights stable associations observed in human genetics studies. It gives an overview of the different types of genetic alterations in these subtypes, including common associations based on genome-wide association studies (GWAS), and it highlights the most frequently observed syndromes associated with ASD pathogenesis.

Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable.

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.

Spontaneous remission of vision degrading myodesopsia of posterior vitreous detachment type.

PURPOSE: The study aims to observe the spontaneous remission of posterior vitreous detachment (PVD)-type vision degrading myodesopsia (VDM) during long-term follow-up. METHODS: We retrospectively reviewed VDM patients with PVD type that refused any treatment. The ratio and time of significant spontaneous remission of floater symptoms occurring were described. The associated factors with significant remission of floater symptoms were analyzed in the univariate and multivariate logistic regression analyses. RESULTS: In total, 179 patients with VDM were assessed. The mean age of all patients was 60.56 ± 0.47 years old, and the mean duration of follow-up was 23.89 ± 6.63 months. Of the patients, 40.78% have significant improvement in their floater symptoms after mean 16.55 ± 10.63-month follow-up. Myopia (OR = 0.280, 95% CI = 0.084-0.932, P = 0.038), the number of floaters > 3 (OR = 0.343, 95% CI = 0.172-0.683, P = 0.002), and floaters with string-like pattern (OR = 0.370, 95% CI = 0.166-0.824, P = 0.015) and blocky pattern (OR = 0.299, 95% CI = 0.090-0.993, P = 0.049) were negatively correlated with the significant spontaneous remission of VDM symptoms in the multiple binary logistic regression analysis. CONCLUSIONS: Approximately 40% of VDM patients with PVD may experience significant spontaneous remission during long-term follow-up. Patients that are non-myopic and with fewer floaters are more likely to feel relief from VDM symptoms. Floaters with string-like or blocky patterns are less likely to undergo spontaneous remission.

Mallory-Weiss syndrome in four hemodialysis patients: a case study.

BACKGROUND: Hemodialysis patients are prone to gastrointestinal bleeding, and Mallory-Weiss syndrome (MWS) is one of the causes. Mallory-Weiss syndrome is often induced by severe vomiting, manifests as upper gastrointestinal bleeding, and is self-limited with a good prognosis. However, mild vomiting in hemodialysis patients can lead to the occurrence of MWS, and the mild early symptoms are easy to misdiagnose, leading to the aggravation of the disease. CASE PRESENTATION: In this paper, we report four hemodialysis patients with MWS. All patients displayed symptoms of upper gastrointestinal bleeding. The diagnosis of MWS was confirmed by gastroscopy. One patient had a history of severe vomiting; however, the other three reported histories of mild vomiting. Three patients received the conservative hemostasis treatment, and the gastrointestinal bleeding stopped. One patient underwent the gastroscopic and interventional hemostasis treatments. The conditions of three of the patients improved. Unfortunately, one of the patients died due to the cardia insufficiency. CONCLUSIONS: We think that the mild symptoms of MWS are easily covered up by other symptoms. This may lead to delays in diagnosis and treatment. For patients with severe symptoms, gastroscopic hemostasis is still the first choice, and interventional hemostasis can also be considered. For patients with mild symptoms, drug hemostasis is the first consideration.

Effect of Past Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder on Substance Use Disorder.

BACKGROUND: Substance use disorders (SUDs) are a considerable public health problem. Attention-deficit/hyperactivity disorder (ADHD) frequently occurs in patients with SUD. Several studies demonstrated that ADHD constitutes a significant risk factor for the development of SUDs and suggest that childhood ADHD pharmacotherapy might help prevent development of SUD. OBJECTIVES: The study aimed to explore the effect of childhood ADHD pharmacotherapy on later life's functional impairment and substance use patterns. METHODS: Treatment-seeking SUD patients with ADHD (n = 52) were recruited from various rehabilitation facilities in South Africa. Adult ADHD individuals without SUD (n = 48) were recruited from clinicians, retail pharmacies, and the general public. SUD participants in rehabilitation facilities were screened for and diagnosed with ADHD. Lifetime substance use was assessed using self-report. ADHD-related functional impairment was assessed by the Weiss Functional Impairment Rating Scale (WFIRS). Information on present and lifetime use of ADHD medication was obtained. Clinical outcomes between those with and without a history of ADHD pharmacotherapy were compared. RESULTS: Medicated participants (n = 59) showed lower levels of ADHD-related impairment across all functional domains (p < 0.001), compared to non-medicated participants (n = 41). They also consumed less alcohol (p = 0.04), cannabis (p < 0.001), and illicit drugs (p = 0.006) compared to the non-medicated group. Furthermore, medicated participants had a lower frequency of tobacco use compared to non-medicated participants (p = 0.04). ADHD patients without SUD also more often received medication (100% vs. 18.6%; p < 0.001) and for a longer time (121.10 vs. 9.52 months; p < 0.001). CONCLUSION: Childhood ADHD pharmacotherapy might be associated with a decreased risk for substance use in adulthood and lower ADHD-related impairment. Despite study limitations, these findings underline the importance of early ADHD detection and treatment, which might prevent SUD.

Talonavicular-cuneiform arthrodesis for the treatment of Müller-Weiss: mid-term results of 15 cases after 5 years.

BACKGROUND: There is no gold standard for the operative treatment of patients with Müller-Weiss disease (MWD). This study reports the mid-term follow-up results for at least 5 years following talonavicular-cuneiform (TNC) arthrodesis for Müller-Weiss disease. METHODS: A total of 15 patients undergoing TNC arthrodesis for MWD were retrospectively reviewed between January 2015 and August 2017. Two senior doctors assessed the radiographic results twice at each visit (preoperative, three months after the operation, and final follow-up). The clinical results and complications from preoperative and final follow-up were recorded. RESULTS: The mean follow up period was 74.0 (range 64 to 90) months. The calcaneal pitch angle, lateral Meary's angle, anteroposterior (AP) Meary's angle, AP talocalcaneal angle, and talonavicular coverage were significantly different before and three months after the operation (p < 0.05). There was no significant difference between the radiographic results of three months after the operation and the final follow-up (p > 0.05). The radiological measurements of the two senior doctors were calculated and found to be moderate to strong (ICC:0.899-0.995). The AOFAS, VAS, and SF-12 scores significantly improved at the last follow-up compared to those before the operation (p < 0.05). Two patients experienced early complications, four had late complications, and one underwent a second operation of midfoot fusion with calcaneal osteotomy. CONCLUSION: This research confirms that using TNC arthrodesis for the treatment of MWD can substantially improve the clinical and radiographic results. These results were maintained until mid-term follow-up.

Towards understanding Müller-Weiss disease from an analysis of 95 cases.

BACKGROUND: The single existing classification of Müller-Weiss Disease (MWD), based solely upon Méary's angle, serves neither as guide for prognosis nor treatment. This accounts for lack of gold standard in its management. METHODS: Navicular compression, medial extrusion, metatarsal lengths, Kite's, lateral and dorsoplantar talo-first metatarsal angles were measured in 95 feet with MWD. Joints involved, presence and location of navicular fracture were recorded. RESULTS: Group 1 "early-onset" MWD feet (n = 11) had greatest compression and medial extrusion, and lowest Kite's angles. All except 1 were index minus and had lateral navicular fracture. Only 1 had moderate degeneration at the talonavicular joint (TNJ) with none requiring surgery yet. Group 2 "Müller-Weissoid" feet (n = 23) had radiologically normal navicular in their fifties and developed MWD on average 5 years later. They had the lowest compression and extrusion, and highest Kite's angles. None had complete fracture. All had TNJ arthritis, with early changes at lateral naviculocuneiform joint (NCJ) in 43%. Group 3 "late-onset" MWD presented in the sixth decade. Only TNJ was involved in Group 3 A (n = 16). Group 3B (n = 20) affected TNJ more than NCJ and had the greatest number of Maceira stage V disease. Group 3 C "reverse Müller-Weiss disease", which affected NCJ more than TNJ (n = 25), had greatest midfoot abduction and overlength of the second metatarsal. No fracture occurred in group 3 A compared to 65% and 32% in groups 3B and 3 C, respectively. CONCLUSIONS: With need to compare like-for-like pathology, the proposed classification provides a common platform for reporting outcomes of different treatments. We theorize pathogenetic pathways in the various groups.

Association of Nrf2 expression and mutation with Weiss and Helsinki scores in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignant tumor. Genetic abnormalities that may represent therapeutic targets and prognostic factors in ACC remain unclear. Besides being one of the main cellular defense mechanisms that regulates antioxidant pathways for detoxifying reactive oxygen species (ROS), the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) promotes tumor proliferation by increasing metabolic activity. In surgical specimens from 12 cases of nonmetastatic ACCs and nine cases of benign adrenocortical adenoma (ACA), we investigated gene mutation and protein expressions for Nrf2 and the preoperative maximum standard glucose uptake (SUVmax) on [18 F]fluorodeoxy-glucose positron emission tomography. Three of five ACCs with a Weiss score of 7 to 9 were Nrf2 mutants; these ACCs had higher expression of Nrf2 and higher preoperative SUVmax. The other seven ACCs had a Weiss score of 3 to 6; these seven ACCs and all the ACAs were non-Nrf2 gene mutants. Patients with a Weiss score of 7 to 9 and Nrf2 mutant ACC had shorter overall survival. Based on Helsinki scoring, three ACCs with a Helsinki score greater than 17 had Nrf2 mutants, higher expression of Nrf2, higher preoperative SUVmax, and shorter overall survival. Our findings indicate that Nrf2 activation and the associated increase in metabolism play roles in ACC, in particular in ACC with a Weiss score of 7 to 9 and a Helsinki score of greater than 17.

Midterm outcomes of midfoot and hindfoot arthrodesis with strut allograft for Müller-Weiss disease.

BACKGROUND: Müller-Weiss disease (MWD), a rare dysplastic disorder of the foot, is characterized by deformity, sclerosis, and fragmentation of the lateral part of navicular bone. Arthrodesis is the mainstay treatment for MWD. Generally, arthrodesis can be achieved through internal fixation with metallic implants, and morselized chip bone may be packed into the gap for better bone union. However, with this procedure, the original foot size is not maintained and support for the foot arch is not provided. Sequela of short foot, or flatfoot is commonly observed even though these complications of surgery had not been reported with cases of MWD treated by arthrodesis. Herein, we present a retrospective analysis of treating MWD through midfoot and hindfoot arthrodesis combined with strut allograft. METHODS: From August 2006 to June 2019, 20 patients with MWD (mean age, 59.6 years; range, 40-80 years) underwent midfoot and hindfoot arthrodesis with strut bone allograft and were followed for at least 24 months. The patients were able to ambulate and participate in rehabilitation programs 3 months postoperatively. RESULTS: The used four radiographic parameters (Meary's angle in anteroposterior and lateral view, talonavicular coverage angle, calcaneal pitch) demonstrated significant differences (P < .05) preoperatively and postoperatively, but those between the postoperative values and the values at the last follow-up session did not, indicating that strut allograft was able to maintain normal alignment. The mean American Orthopaedic Foot & Ankle Society Ankle-Hindfoot scores at 2 years postoperatively revealed significant improvement from baseline, from 60.2 to 84.2 (P < .05). The 12-item Short Form Health Survey scores also improved significantly (P < .05). All patients reported substantial pain relief and exhibited improved functional outcomes and gait patterns. CONCLUSIONS: For advanced-stage MWD, arthrodesis with a precisely shaped, size-matched strut allograft provided strong support for biomechanical alignment and enhanced functional performance.

Efficacy of Triple and Talonavicular Arthrodesis for the Treatment of III-V Müller-Weiss Disease.

Müller-Weiss Disease (MWD) is a rare foot disease with unclear etiology but frequently occurred in women. Due to the resistance to conservative treatment, surgical therapy has gradually occupied a necessary position in the clinical management of MWD. Joint fusion surgery is a commonly used treatment for MWD, which could effectively alleviate pain, correct deformation, and restore function. A total of 12 MWD patients (III-V stage) were enrolled in this study. All patients showed no significant improvement in conservative treatment and further received the triple and talonavicular arthrodesis. All patients were followed up with an average follow-up of 16.8 ± 1.19 months (mean ± SD). The triple and talonavicular arthrodesis significantly ameliorated the pain and walking dysfunction in the affected foot. The American Orthopedic Foot Andankle Society (AOFAS) scores dramatically increased from 43.4 ± 16.1 to 85.3 ± 6.2. Meanwhile, the conducting of triple and talonavicular arthrodesis improved the X-ray length (15.5 ± 0.8 vs. 14.3 ± 0.9 cm) and arch height (18.6 ± 0.9 vs. 10.2 ± 0.7 mm) and reduced the Meary-Tomeno angle (1.3 ± 2.5 vs. 2.14 ± 4.8°). The triple and talonavicular arthrodesis achieved a satisfying therapeutic effect on MWD patients at the III-V stage, which improved patients' outcomes and the quality of life.

Severe craniolacunae and upper and lower extremity anomalies resulting from Crouzon syndrome, FGFR2 mutation, and Ser347Cys variant.

Crouzon syndrome is a rare form of syndromic craniosynostosis (SC) characterized by premature fusion of the cranial and facial sutures, elevated intracranial pressure, varying degrees of ocular exposure due to exorbitism, and airway compromise caused by midface retrusion. Craniolacunae and upper and lower extremity anomalies are not frequently found in Crouzon syndrome. We present a girl with Crouzon syndrome caused by c.1040 C > G, p.Ser347Cys, a pathogenic mutation in the FGFR2 gene with atypical characteristics, including craniolacunae resembling severe Swiss cheese type of bone formation, and upper and lower extremity anomalies which are more commonly associated with Pfeiffer syndrome patients. Distinguishing between severe Crouzon syndrome patients and patients who have mild and/or moderate Pfeiffer syndrome can be challenging even for an experienced craniofacial surgeon. An accurate genotype diagnosis is essential to distinguishing between these syndromes, as it provides predictors for neurosurgical complications and facilitates appropriate family counseling related to long-term outcomes.

Empty Sella Syndrome Associated with Growth Hormone Deficiency: the First Case Report of Weiss-Kruszka Syndrome.

Weiss-Kruszka syndrome (WSKA), caused by heterozygous loss-of-function variants in ZNF462 gene, is a recently described and extremely rare genetic disorder. The main phenotypes include characteristic craniofacial features, ptosis, dysgenesis of the corpus callosum, and neurodevelopmental impairment. We report the first Korean boy with molecularly confirmed WSKA presenting with an atypical manifestation. A 16-year-old boy with a history of bilateral ptosis surgery presented with short stature (-3.49 standard deviation score) and delayed puberty. The patient showed characteristic craniofacial features including an inverted triangular-shaped head, exaggerated Cupid's bow, arched eyebrows, down-slanting palpebral fissures, and poorly expressive face. He had a mild degree of intellectual disability and mild hypotonia. Endocrine studies in the patient demonstrated complete growth hormone deficiency (GHD) associated with empty sella syndrome (ESS), based on a magnetic resonance imaging study for the brain that showed a flattened pituitary gland and cerebrospinal fluid space herniated into the sella turcica. To identify the genetic cause, we performed whole exome sequencing (WES). Through WES, a novel de novo heterozygous nonsense variant, c.4185del; p.(Met1396Ter) in ZNF462 was identified. This is the first case of WSKA accompanied by primary ESS associated with GHD. More clinical and functional studies are needed to elucidate this association.

Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses.

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement.

Psychometric properties of the Weiss Functional Impairment Rating Scale parent and self-reports in a Norwegian clinical sample of adolescents treated for ADHD.

OBJECTIVE: To analyze the psychometric properties of the Norwegian version of the Weiss Functional Impairment Rating Scale parent and self-reports (WFIRS-P and WFIRS-S) in adolescents with ADHD. METHODS: 102 clinically referred patients, of which 86% were enrolled in an ongoing RCT program (Clinical trials NCT02937142), were diagnosed with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV). The conceptual framework of the WFIRS-P and the WFIRS-S was evaluated using confirmatory factor analysis (CFA), reliability was estimated using Cronbach's alpha, convergent and divergent validity was assessed using correlations with the Children's Global Assessment Scale (C-GAS) and the ADHD Rating Scale-IV (ADHD-RS-IV). RESULTS: CFA supported the original factor structure of the questionnaires, both a first-order and a second-order model revealed acceptable model fit. Internal consistency was satisfactory across domains. The parent-adolescent agreement was moderate. The correlations between the C-GAS and the total scores of the WFIRS-P and WFIRS-S were low to moderate (r = -0.29 to -0.38). The ADHD-RS-IV correlated moderately (r = 0.49) with WFIRS-P, the correlation with WFIRS-S was weak (r = 0.28) supporting divergent validity. In multiple regression analyses, the ADHD-RS total score was the strongest predictor of the total score in both the WFIRS questionnaires, with internalizing disorder showing an additional small contribution. Age, gender and full-scale IQ gave no additional contribution in explaining the variance. CONCLUSIONS: The findings support the use of the Norwegian version of the WFIRS-S and the WFIRS-P in the evaluation of functional impairment in adolescents with ADHD.

[Myxoid variant of adrenocortical carcinoma]. / Carcinome corticosurrénalien variante myxoïde : aspects clinico-pathologiques et immunohistochimiques d'une variante rare et agressive.

We report two cases of patients presenting myxoid variant of adrenocortical carcinoma (ACC). This very rare variant is characterized by a tumoral proliferation organized in trabeculae, cords or even pseudo-glands within an acellular myxoid materiel stained by Alcian Blue and negative for PAS. Tumor cells have a small to medium size and have little atypia. Their immunohistochemical profil (positivity of Synaptophysin, SF1, Melan A, Vimentin and Inhibin, with a weak or negative pancytokeratin expression) eliminate the main differential diagnoses (metastasis of a myxoid adenocarcinoma and soft tissue myxoid tumor). Many scoring systems have been proposed in order to evaluate the risk of malignancy of these lesions: the Weiss score seems less efficient to evaluate malignancy in this variant than the reticulinic algorithm or the Helsinki score. Prognosis of myxoid variant of ACC seems worse than classical ACC.

Radiographic analysis of Müller-Weiss disease.

BACKGROUND: The only classification of Müller-Weiss disease (MWD) is based primarily on Méary's talo-first metatarsal angle. It describes increasing sag of the medial longitudinal arch with greater degrees of compression and fragmentation of the navicular. Purportedly, the talar head pushes the subtalar joint into varus and drives the medial pole of the navicular medially, as it protrudes inferiorly and laterally. Its authors stipulated heel varus as a pre-requisite, coining the term 'paradoxical pes planus varus' to define heel varus and flatfoot as hallmark deformities of the condition. METHODS: We measured Méary's and Kite's talocalcaneal angles, heel offset, anteroposterior thickness of the navicular at each naviculocuneiform (NC) joint, medial extrusion of the navicular and calculated percentage compression at each NC joint in 68 consecutive feet presenting with MWD. Morphology and activity at the various peri-navicular joints were studied using SPECT-CT in 45 feet. RESULTS: Inverse relationships between Méary's angle and degree of navicular compression reach statistical significance at NC2 but not at NC3. Strong correlation exists between medial extrusion and percentage compression at NC2 and NC3. Medial extrusion is significantly greater on the affected side in unilateral cases and on the more compressed side in bilateral cases. Significant inverse relationships exist between Kite's angle and percentage compression at both NC2 and NC3 and degree of medial extrusion of the navicular. No correlation was detected between Kite's angle and either heel offset or Méary's angle. Varus heel offset was present in only 33% of cases. The combination of heel varus and negative Méary's angle was present in just 26% of cases, the commonest combination being heel valgus with sagging at 56%. CONCLUSION: Our findings confirm part of Maceira's hypothesized pathomechanism of MWD. Reductions in Kite's talocalcaneal angle confirm that lateral and inferior protrusion of the talar head causes increasing compression and medial extrusion of the navicular. However, such shift of the talar head does not always lead to heel varus. As such, we caution against universal advocacy of lateral displacement calcaneal osteotomy, as the heel is not always in varus in MWD.

Identifying the reactive sites of hydrogen peroxide decomposition and hydroxyl radical formation on chrysotile asbestos surfaces.

BACKGROUND: Fibrous chrysotile has been the most commonly applied asbestos mineral in a range of technical applications. However, it is toxic and carcinogenic upon inhalation. The chemical reactivity of chrysotile fiber surfaces contributes to its adverse health effects by catalyzing the formation of highly reactive hydroxyl radicals (HO•) from H2O2. In this Haber-Weiss cycle, Fe on the fiber surface acts as a catalyst: Fe3+ decomposes H2O2 to reductants that reduce surface Fe3+ to Fe2+, which is back-oxidized by H2O2 (Fenton-oxidation) to yield HO•. Chrysotile contains three structural Fe species: ferrous and ferric octahedral Fe and ferric tetrahedral Fe (Fe3+tet). Also, external Fe may adsorb or precipitate onto fiber surfaces. The goal of this study was to identify the Fe species on chrysotile surfaces that catalyze H2O2 decomposition and HO• generation. RESULTS: We demonstrate that at the physiological pH 7.4 Fe3+tet on chrysotile surfaces substantially contributes to H2O2 decomposition and is the key structural Fe species catalyzing HO• generation. After depleting Fe from fiber surfaces, a remnant fiber-related H2O2 decomposition mode was identified, which may involve magnetite impurities, remnant Fe or substituted redox-active transition metals other than Fe. Fe (hydr)oxide precipitates on chrysotile surfaces also contributed to H2O2 decomposition, but were per mole Fe substantially less efficient than surface Fe3+tet. Fe added to chrysotile fibers increased HO• generation only when it became incorporated and tetrahedrally coordinated into vacancy sites in the Si layer. CONCLUSIONS: Our results suggest that at the physiological pH 7.4, oxidative stress caused by chrysotile fibers largely results from radicals produced in the Haber-Weiss cycle that is catalyzed by Fe3+tet. The catalytic role of Fe3+tet in radical generation may also apply to other pathogenic silicates in which Fe3+tet is substituted, e.g. quartz, amphiboles and zeolites. However, even if these pathogenic minerals do not contain Fe, our results suggest that the mere presence of vacancy sites may pose a risk, as incorporation of external Fe into a tetrahedral coordination environment can lead to HO• generation.

Psychometric properties of a modified version of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) in a clinical sample of children with aggressive behavior.

PURPOSE: To evaluate the psychometric properties of a German modification of the Weiss Functional Impairment Rating Scale-Parent Report for children with aggressive and oppositional behavior problems (WFIRS-P for ODD/CD). METHODS: Data were collected from a clinical sample of children (6-12 years; 96% boys) with oppositional defiant disorder (ODD) and conduct disorder (CD) (N = 219). The WFIRS-P conceptual framework was evaluated using confirmatory factor analyses (CFA). Reliability was estimated using internal consistency (Cronbach's alpha) and omega statistics. Validity was assessed through correlations between WFIRS-P for ODD/CD domain scores and parent-rated scales on symptoms of ODD, CD, attention-deficit/hyperactivity disorder (ADHD), a broad range of other behavioral and emotional problems, and scales on health-related quality of life and family burden. RESULTS: CFA of the WFIRS-P for ODD/CD revealed that a bifactor model, with a general factor accounting for common variance (ωH = 0.23-0.48) and independent specific group factors accounting for additional variance in item scores (ωS = 0.37-0.60), best fits the data. Thus, CFA confirmed the theoretical assumption of a general construct of impairment (total scale) and additional specific impairments (subscales, e.g., family, social activities). Cronbach's alpha coefficient exceeded 0.70 for all subscales. Omega statistics showed that both the general construct and specific factors accounted for item variance. As expected, correlations with symptoms scales for ODD/CD and ADHD were low to moderate. CONCLUSIONS: The use of the parent-rated WFIRS for ODD/CD in identifying ODD- and CD-related impairment in children is psychometrically supported. The scale can be employed to assess functional impairment in children with aggressive behavior problems.