Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings.

We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of "brain abnormalities, neurodegeneration, and dysosteosclerosis" (BANDDOS) and discuss its link with "adult leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.

Comparison of Commercial AI Software Performance for Radiograph Lung Nodule Detection and Bone Age Prediction.

Background Multiple commercial artificial intelligence (AI) products exist for assessing radiographs; however, comparable performance data for these algorithms are limited. Purpose To perform an independent, stand-alone validation of commercially available AI products for bone age prediction based on hand radiographs and lung nodule detection on chest radiographs. Materials and Methods This retrospective study was carried out as part of Project AIR. Nine of 17 eligible AI products were validated on data from seven Dutch hospitals. For bone age prediction, the root mean square error (RMSE) and Pearson correlation coefficient were computed. The reference standard was set by three to five expert readers. For lung nodule detection, the area under the receiver operating characteristic curve (AUC) was computed. The reference standard was set by a chest radiologist based on CT. Randomized subsets of hand (n = 95) and chest (n = 140) radiographs were read by 14 and 17 human readers, respectively, with varying experience. Results Two bone age prediction algorithms were tested on hand radiographs (from January 2017 to January 2022) in 326 patients (mean age, 10 years ± 4 [SD]; 173 female patients) and correlated strongly with the reference standard (r = 0.99; P < .001 for both). No difference in RMSE was observed between algorithms (0.63 years [95% CI: 0.58, 0.69] and 0.57 years [95% CI: 0.52, 0.61]) and readers (0.68 years [95% CI: 0.64, 0.73]). Seven lung nodule detection algorithms were validated on chest radiographs (from January 2012 to May 2022) in 386 patients (mean age, 64 years ± 11; 223 male patients). Compared with readers (mean AUC, 0.81 [95% CI: 0.77, 0.85]), four algorithms performed better (AUC range, 0.86-0.93; P value range, <.001 to .04). Conclusions Compared with human readers, four AI algorithms for detecting lung nodules on chest radiographs showed improved performance, whereas the remaining algorithms tested showed no evidence of a difference in performance. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Omoumi and Richiardi in this issue.

Staphylococcus epidermidis isolates from atopic or healthy skin have opposite effect on skin cells: potential implication of the AHR pathway modulation.

Introduction: Staphylococcus epidermidis is a commensal bacterium ubiquitously present on human skin. This species is considered as a key member of the healthy skin microbiota, involved in the defense against pathogens, modulating the immune system, and involved in wound repair. Simultaneously, S. epidermidis is the second cause of nosocomial infections and an overgrowth of S. epidermidis has been described in skin disorders such as atopic dermatitis. Diverse isolates of S. epidermidis co-exist on the skin. Elucidating the genetic and phenotypic specificities of these species in skin health and disease is key to better understand their role in various skin conditions. Additionally, the exact mechanisms by which commensals interact with host cells is partially understood. We hypothesized that S. epidermidis isolates identified from different skin origins could play distinct roles on skin differentiation and that these effects could be mediated by the aryl hydrocarbon receptor (AhR) pathway. Methods: For this purpose, a library of 12 strains originated from healthy skin (non-hyperseborrheic (NH) and hyperseborrheic (H) skin types) and disease skin (atopic (AD) skin type) was characterized at the genomic and phenotypic levels. Results and discussion: Here we showed that strains from atopic lesional skin alter the epidermis structure of a 3D reconstructed skin model whereas strains from NH healthy skin do not. All strains from NH healthy skin induced AhR/OVOL1 path and produced high quantities of indole metabolites in co-culture with NHEK; especially indole-3-aldehyde (IAld) and indole-3-lactic acid (ILA); while AD strains did not induce AhR/OVOL1 path but its inhibitor STAT6 and produced the lowest levels of indoles as compared to the other strains. As a consequence, strains from AD skin altered the differentiation markers FLG and DSG1. The results presented here, on a library of 12 strains, showed that S. epidermidis originated from NH healthy skin and atopic skin have opposite effects on the epidermal cohesion and structure and that these differences could be linked to their capacity to produce metabolites, which in turn could activate AHR pathway. Our results on a specific library of strains provide new insights into how S. epidermidis may interact with the skin to promote health or disease.

A Healthcare Physician Can Be Trained to Perform Intestinal Ultrasound in Children With Inflammatory Bowel Disease.

OBJECTIVES: Training healthcare physicians to perform intestinal ultrasound (IUS) during outpatient visits with equal accuracy as radiologists could improve clinical management of IBD patients. We aimed to assess whether a healthcare-physician can be trained to perform IUS, with equal accuracy compared with experienced radiologists in children with iBD, and to assess inter-observer agreement. METHODS: Consecutive children, 6 to 18 years with IBD or suspicion of IBD, who underwent ileo-colonoscopy were enrolled. iUS was performed independently by a trained healthcare-physician and a radiologist in 1 visit. Training existed of an international training curriculum for IUS. Operators were blinded for each other's IUS, and for the ileocolonoscopy. Difference in accuracy of IUS by the healthcare-physician and radiologist was assessed using areas under the ROC curve (AUROC). Inter-observer variability was assessed in terminal ileum (TI), transverse colon (TC) and descending-colon (DC), for disease activity (ie, bowel wall thickness [BWT] >2 mm with hyperaemia or fat-proliferation, or BWT >3 mm). RESULTS: We included 73 patients (median age 15, interquartile range [IQR]:13-17, 37 [51%] female, 43 [58%] with Crohn disease). AUROC ranged between 0.71 and 0.81 for the healthcare-physician and between 0.67 and 0.79 for radiologist (P  > 0.05). Inter-observer agreement for disease activity per segment was moderate (K: 0.58 [SE: 0.09], 0.49 [SE: 0.12], 0.52 [SE: 0.11] respectively for TI, TC, and DC). CONCLUSIONS: A healthcare- physician can be trained to perform IUS in children with IBD with comparable diagnostic accuracy as experienced radiologists. The interobserver agreement is moderate. Our findings support the usage of IUS in clinical management of children with IBD.

Complete Genome Sequence of Sphingobium xenophagum PH3-15, Isolated from La Roche-Posay Thermal Water Sources.

We report here the complete genome sequence of Sphingobium xenophagum strain PH3-15, which was isolated from La Roche-Posay thermal water sources. The assembled 4.6-Mbp genome consisted of two chromosomes and three plasmids. These data will provide valuable information and important insights into the physiology and metabolism of this Sphingobium organism.

An Adolescent with Transient Hyperthyroxinemia after Blunt Trauma to Head and Neck.

BACKGROUND: Thyroid storm is a well-known complication of surgical procedures in the lower neck, but is rare after a blunt neck trauma. The cases described previously have mainly focussed on adults with pre-existent thyroid disease. In this case report, we describe the disease course of a previously healthy adolescent who had asymptomatic hyperthyroxinemia after a blunt trauma of the jaw and neck. Case Presentation. A 17-year-old girl presented at our emergency department after she fell on her head while roller blading. On physical examination, among other injuries, she had a swelling in the lower neck, which appeared to involve the thyroid gland. Subsequent laboratory analysis was indicative of primary hyperthyroxinemia, with a free T4 of 59 pmol/L (reference range: 12-22) and a TSH of 0.46 mU/L (reference range: 0.5-4.3), but the patient had no symptoms fitting with this. Four weeks after the initial presentation, the patient reported only complaints regarding tenderness in the jaw and neck region. She was no longer hyperthyroidic on biochemical evaluation (with a free T4 level of 15.6 pmol/L and a TSH level of 0.33 mU/L), and antibodies against thyroid peroxidase or TSH receptor were not present. CONCLUSIONS: This case might indicate that hyperthyroxinemia following a neck trauma may go unnoticed if hyperthyroid symptoms are mild or absent and thyroid function tests are not performed.

Engineering the Yeast Yarrowia lipolytica for Production of Polylactic Acid Homopolymer.

Polylactic acid is a plastic polymer widely used in different applications from printing filaments for 3D printer to mulching films in agriculture, packaging materials, etc. Here, we report the production of poly-D-lactic acid (PDLA) in an engineered yeast strain of Yarrowia lipolytica. Firstly, the pathway for lactic acid consumption in this yeast was identified and interrupted. Then, the heterologous pathway for PDLA production, which contains a propionyl-CoA transferase (PCT) converting lactic acid into lactyl-CoA, and an evolved polyhydroxyalkanoic acid (PHA) synthase polymerizing lactyl-CoA, was introduced into the engineered strain. Among the different PCT proteins that were expressed in Y. lipolytica, the Clostridium propionicum PCT exhibited the highest efficiency in conversion of D-lactic acid to D-lactyl-CoA. We further evaluated the lactyl-CoA and PDLA productions by expressing this PCT and a variant of Pseudomonas aeruginosa PHA synthase at different subcellular localizations. The best PDLA production was obtained by expressing the PCT in the cytosol and the variant of PHA synthase in peroxisome. PDLA homopolymer accumulation in the cell reached 26 mg/g-DCW, and the molecular weights of the polymer (Mw = 50.5 × 103 g/mol and Mn = 12.5 × 103 g/mol) were among the highest reported for an in vivo production.

Fetal MRI, lower acceptance by women in research vs. clinical setting.

AIM: To determine acceptance of pregnant women to undergo fetal magnetic resonance imaging (MRI) examination in research and clinical setting. METHODS: A prospective study included a research group [part of a study comparing brain ultrasound (US) to MRI in fetuses at risk for acquired brain damage] and a clinical group [fetuses with suspected (brain) anomalies after structural US examination] from 2011 to 2014. All women were advised to use sedatives. MRI declinations, use of sedation, MRI duration and imaging quality were compared between both groups. RESULTS: Study participation was accepted in 57/104 (55%) research cases. Fetal MRI was performed in 34/104 (33%) research and 43/44 (98%) clinical cases. Reasons to decline study participation were MRI related in 41%, and participation was too burdensome in 46%. Acceptance was highest for indication infection and lowest in alloimmune thrombocytopenia and monochorionic twin pregnancy. Sedatives were used in 14/34 research and 43/43 clinical cases. Scan duration and quality were comparable (21 and 20 min in research and clinical cases, respectively, moderate/good quality in both groups). CONCLUSIONS: Pregnant women consider MRI more burdensome than professionals realize. Two-third of women at risk for fetal brain damage decline MRI examination. Future studies should evaluate which information about fetal MRI is supportive.

A metabolic engineering strategy for producing conjugated linoleic acids using the oleaginous yeast Yarrowia lipolytica.

Conjugated linoleic acids (CLAs) have been found to have beneficial effects on human health when used as dietary supplements. However, their availability is limited because pure, chemistry-based production is expensive, and biology-based fermentation methods can only create small quantities. In an effort to enhance microbial production of CLAs, four genetically modified strains of the oleaginous yeast Yarrowia lipolytica were generated. These mutants presented various genetic modifications, including the elimination of ß-oxidation (pox1-6∆), the inability to store lipids as triglycerides (dga1∆ dga2∆ are1∆ lro1∆), and the overexpression of the Y. lipolytica ∆12-desaturase gene (YlFAD2) under the control of the constitutive pTEF promoter. All strains received two copies of the pTEF-oPAI or pPOX-oPAI expression cassettes; PAI encodes linoleic acid isomerase in Propionibacterium acnes. The strains were cultured in neosynthesis or bioconversion medium in flasks or a bioreactor. The strain combining the three modifications mentioned above showed the best results: when it was grown in neosynthesis medium in a flask, CLAs represented 6.5% of total fatty acids and in bioconversion medium in a bioreactor, and CLA content reached 302 mg/L. In a previous study, a CLA degradation rate of 117 mg/L/h was observed in bioconversion medium. Here, by eliminating ß-oxidation, we achieved a much lower rate of 1.8 mg/L/h.

Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma.

Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0-61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.

Trends and patterns of computed tomography scan use among children in The Netherlands: 1990-2012.

OBJECTIVE: To evaluate trends and patterns in CT usage among children (aged 0-17 years) in The Netherlands during the period 1990-2012. METHODS: Lists of electronically archived paediatric CT scans were requested from the Radiology Information Systems (RIS) of Dutch hospitals which reported >10 paediatric CT scans annually in a survey conducted in 2010. Data included patient identification, birth date, gender, scan date and body part scanned. For non-participating hospitals and for years prior to electronic archiving in some participating hospitals, data were imputed by calendar year and hospital type (academic, general with <500 beds, general with ≥ 500 beds). RESULTS: Based on 236,066 CT scans among 146,368 patients performed between 1990 and 2012, estimated annual numbers of paediatric CT scans in The Netherlands increased from 7,731 in 1990 to 26,023 in 2012. More than 70 % of all scans were of the head and neck. During the last decade, substantial increases of more than 5 % per year were observed in general hospitals with fewer than 500 beds and among children aged 10 years or older. CONCLUSION: The estimated number of paediatric CT scans has more than tripled in The Netherlands during the last two decades. KEY POINTS: • Paediatric CT in The Netherlands has tripled during the last two decades. • The number of paediatric CTs increased through 2012 in general hospitals. • Paediatric CTs continued to increase among children aged 10 years or older.

Prevesical Calcification and Hydronephrosis in a Girl Treated for Vesicoureteral Reflux.

The endoscopic STING procedure using Deflux is a common and minimal invasive treatment for vesicoureteral reflux. Herein we present the case of an 11-year-old girl with loin pain and de novo hydronephrosis and megaureter on the left. Ultrasound and plain abdominal X-ray demonstrated a calcification at the ureterovesical junction. She had been treated with Deflux injections 5 years before. The clinical quiz addresses the differential diagnosis, workup, and pathogenesis of calcifications at the ureterovesical junction following endoscopic reflux therapy.

Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy.

OBJECTIVES: To assess frequency of gallbladder polyposis and carcinoma in metachromatic leukodystrophy (MLD). METHODS: We evaluated 34 patients with MLD (average age 16.7 years, age range 2-39 years) screened for gallbladder abnormalities by ultrasound. In the case of cholecystectomy, findings at pathology were reviewed. RESULTS: Only 8 of 34 patients (23%) had a normal gallbladder at ultrasound. Gallbladder polyps were visible in 8 patients (23%). Cholecystectomy was performed in 11 patients (32%). In these, pathology revealed various abnormalities, including hyperplastic polyps, intestinal metaplasia, prominent Rokitansky-Aschoff sinuses, and sulfatide storage. CONCLUSIONS: Our results demonstrate that gallbladder involvement is the rule rather than the exception in MLD. The high prevalence of hyperplastic polyps, a known precancerous condition, and one death from gallbladder carcinoma at a young age suggest that MLD predisposes to neoplastic gallbladder abnormalities. As novel therapies for this patient group are emerging leading to increased life expectancy, we recommend screening for gallbladder abnormalities by ultrasound in order to prevent early death.

The value of ultrasonography in boys with a non-palpable testis.

BACKGROUND: In patients with a non-palpable testis (NPT) on physical examination, the testis is assumed either to be situated intra-abdominally or to be hypoplastic or absent. Diagnostic laparoscopy in these boys is considered the preferable first step. In this study the diagnostic value of pre-operative ultrasound for NPT is assessed in comparison with laparoscopy. METHODS: All boys aged under the age of 17 years who were diagnosed with an NPT by a pediatric surgeon from 2000 till 2012 were evaluated. All patients of whom clinical, ultrasonographic, and operative findings were available were included. RESULTS: Ninety-six boys with 117 NPTs were included. With ultrasound 67 testes were detected in the inguinal canal, which was confirmed peroperatively for 61 testes. Of the 15 testes with an intra-abdominal position on ultrasound, 10 were found intra-abdominally during surgery. The positive predictive value of the ultrasonography is 91% for inguinally located testes and 67% for intra-abdominally located testes. CONCLUSION: Ultrasonography has a high positive predictive value for inguinally located testes. When ultrasound locates a testis in an inguinal location, a primary inguinal exploration can be considered, preventing an unnecessary diagnostic laparoscopy.

Anuria in a solitary kidney with Candida bezoars managed conservatively.

UNLABELLED: Renal involvement is regularly encountered in neonates with invasive candidiasis, especially when risk factors like congenital malformations of the renal tract or poor bladder emptying and preterm birth are present. However, complete obstruction of the renal collecting system by fungal balls is rare. Although conservative management has been advocated for partial obstruction, complete obstruction is considered an indication for surgical drainage. We report a patient with anuria and Candida albicans bezoars in a solitary kidney, suggesting post-renal acute kidney injury. The patient was treated with systemic fluconazole and peritoneal dialysis for 4 days. The fungus balls disappeared and renal function recovered. CONCLUSION: Systemic antifungal therapy leads to clearance of obstructing fungus balls, and nephrostomy should be reserved for anuria due to bilateral complete obstruction with severe hydronephrosis. In these cases, temporary dialysis is a potential alternative.

Optimized invertase expression and secretion cassette for improving Yarrowia lipolytica growth on sucrose for industrial applications.

Yarrowia lipolytica requires the expression of a heterologous invertase to grow on a sucrose-based substrate. This work reports the construction of an optimized invertase expression cassette composed of Saccharomyces cerevisiae Suc2p secretion signal sequence followed by the SUC2 sequence and under the control of the strong Y. lipolytica pTEF promoter. This new construction allows a fast and optimal cleavage of sucrose into glucose and fructose and allows cells to reach the maximum growth rate. Contrary to pre-existing constructions, the expression of SUC2 is not sensitive to medium composition in this context. The strain JMY2593, expressing this new cassette with an optimized secretion signal sequence and a strong promoter, produces 4,519 U/l of extracellular invertase in bioreactor experiments compared to 597 U/l in a strain expressing the former invertase construction. The expression of this cassette strongly improved production of invertase and is suitable for simultaneously high production level of citric acid from sucrose-based media.

Second cranio-facial malignancies in hereditary retinoblastoma survivors previously treated with radiation therapy: clinic and radiologic characteristics and survival outcomes.

INTRODUCTION: Hereditary retinoblastoma survivors have an increased risk for cranio-facial second primary tumours (SPT), especially after treatment with external beam radiotherapy (EBRT). This multicentre study evaluates the clinical and imaging characteristics and outcomes of cranio-facial SPTs in irradiated retinoblastoma survivors. PATIENTS AND METHODS: Clinical and radiological data of 42 hereditary retinoblastoma patients with 44 second and third malignancies were reviewed. Radiological data included anatomic location and computed tomography (CT) and magnetic resonance (MR) characteristics. Cox regression and likelihood ratio chi-square test were used to evaluate differences in patients' survival rates. RESULTS: Cranio-facial SPTs were diagnosed at a median age of 13 years. Histological types included osteosarcomas (43%), rhabdomyosarcomas (20%) (57% embryonal, 43% alveolar) and a variety of other types of SPT (37%). Predilection sites were: temporal fossa (39%), ethmoid sinus (23%), orbit (18%), maxillary sinus (16%) and intracranial dura mater (4%). Most of the osteosarcomas (78%) and rhabdomyosarcomas (80%) occurred in patients treated with EBRT in the first year-of-life. Treatment of SPTs with a microscopically complete surgical resection led to a significantly better 5-year overall survival (OS) (P=0.017) and event-free survival (EFS) (P=0.012) compared to patients treated without surgery or incomplete resection (OS: 83% versus 52%; EFS: 80% versus 47%). CONCLUSIONS: Osteosarcomas and rhabdomyosarcomas are the most common cranio-facial SPTs in irradiated hereditary retinoblastoma survivors, which develop in specific locations and occur predominantly in patients irradiated in their first year-of-life. Microscopically complete surgical resection of SPTs is a major prognostic factor, suggesting the potential benefit of early detection by imaging.

Efficient homologous recombination with short length flanking fragments in Ku70 deficient Yarrowia lipolytica strains.

In Yarrowia lipolytica, targeted gene replacement occurs only with long length (1 kb) homologous flanking fragments, as this yeast preferentially uses the non-homologous end-joining mechanism (NHEJ) for DNA repair over homologous recombination (HR). To improve the frequency of HR, we identified and disrupted the KU70 and KU80 genes responsible for double strand break repair in the NHEJ pathway in Y. lipolytica. In ku70∆ HR of URA3 marker at the ADE2 locus occurred with 43 % frequency with as little as 50 bp long flanking regions. The number of Ura(+) transformants was reduced to 1 % of the Po1d (ura3-302) wild type-like strain level, regardless of the flanking fragment length. On the contrary, even though HR was not improved in ku80∆, Ura(+) transformants was 60 % lower compared to the wild type.

A novel GJC2 mutation associated with hypomyelination and Müllerian agenesis syndrome: coincidence or a new entity?

In recent years, several new white matter diseases have been identified based on magnetic resonance imaging and clinical findings. For most newly defined disorders the genetic basis has been identified. However, there is still a large group of patients without a specific diagnosis. Hypomyelinating leukodystrophies are the largest group among them. In some disorders characterized by hypomyelination only central nervous system involvement is observed, but in some disorders involvement of other organs is observed as well, such as eyes or teeth. Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, ataxia, and progressive spasticity. The disease is caused by mutations in GJC2, the gene that encodes the gap junction protein connexin 47. Here we describe hypomyelination and Müllerian agenesis syndrome in a girl who is homozygous for a novel mutation in the GJC2 gene. It is an open question whether this is an association by chance or a feature of PMLD not previously noted.

Kaposiform (spindle cell) hemangioendotelioma in a child with an unusual presentation.

We describe a male child with multifocal kaposiform hemangioendothelioma in the right and left cervical region with development of Kasabach-Merritt syndrome. Treatment with interferon-alpha resulted in a good but only temporary clinical response.He relapsed 3 times with regrowth of the right cervical tumor. Involvement of the liver is suspected, because normalization of the liver size followed after the treatment with interferon-alpha. The question remains whether the multiple osteolytic bone lesions also reflect kaposiform hemangioendothelioma localization.