Risk factors and clinical characteristics of acute and chronic cutaneous graft-versus-host disease in pediatric patients undergoing hematopoietic stem cell transplantation.

Acute and chronic cutaneous graft-versus-host disease (GVHD) are common complications following hematopoietic stem cell transplantation (HSCT) in pediatric patients. In this retrospective study, we explored the risk factors and clinical characteristics of acute and chronic cutaneous GVHD in a case series of children undergoing HSCT at a tertiary referral hospital. We found that 36% of acute cutaneous GVHD was severe and these patients were more likely to have an unrelated donor, and that children with acute cutaneous GVHD who progressed to chronic cutaneous GVHD had a higher proportion of malignant diseases, total body irradiation, and bronchiolitis obliterans compared to those who did not progress to chronic cutaneous GVHD. Our study highlights the importance of identifying and monitoring these high-risk patients to improve the clinical management and outcomes of cutaneous GVHD in pediatric HSCT recipients.

[Twin gestation with complete hydatidiform mole and a coexisting live fetus: A case report and review of the literature]. / Embarazo gemelar con mola hidatiforme completa y feto vivo asociado: reporte de un caso y revisión bibliográfica.

Twin pregnancies with complete hydatidiform mole and coexisting live fetus are very rare, with only about 300 reported cases. This type of pregnancy is considered a high obstetric risk due to the possibility of severe maternal-fetal complications. Although the clinical and ultrasound findings can be highly suggestive of this type of pregnancy, the definitive diagnosis is usually reached by histopathological examination. The differential diagnosis usually includes partial hydatidiform mole and hydropic pregnancies, which can present similar findings in specimens from the first trimester of pregnancy and thus it is important to interpret correctly the differentiating features. The use of immunohistochemistry for p57 can prove very useful, although some cases show an aberrant expression. We present a case of a twin pregnancy with complete hydatidiform mole associated with a live fetus, with magnetic resonance imaging and ultrasound for radiopathological correlation. We discuss the differential diagnosis and the utility of p57 immunohistochemistry.

Identification of a Golgi-localized peptide reveals a minimal Golgi-targeting motif.

Prior work has identified signal sequences and motifs that are necessary and sufficient to target proteins to specific subcellular regions and organelles such as the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria. In contrast, minimal sequence motifs that are sufficient for Golgi localization remain largely elusive. In this work, we identified a 37-amino acid alternative open reading frame (altORF) within the mRNA of the centromere protein CENP-R. This altORF peptide localizes specifically to the cytoplasmic surface of the Golgi apparatus. Through mutational analysis, we identify a minimal 10-amino acid sequence and a critical cysteine residue that are necessary and sufficient for Golgi localization. Pharmacological perturbations suggest that this peptide undergoes lipid modification to promote its localization. Together, our work defines a minimal sequence that is sufficient for Golgi targeting and provide a valuable Golgi marker for live cell imaging.

Dynamic cell cycle-dependent phosphorylation modulates CENP-L-CENP-N centromere recruitment.

The kinetochore is a macromolecular structure that is needed to ensure proper chromosome segregation during each cellular division. The kinetochore is assembled upon a platform of the 16-subunit constitutive centromere-associated network (CCAN), which is present at centromeres throughout the cell cycle. The nature and regulation of CCAN assembly, interactions, and dynamics needed to facilitate changing centromere properties and requirements remain to be fully elucidated. The CENP-LN complex is a CCAN component that displays unique cell cycle-dependent localization behavior, peaking in the S phase. Here, we demonstrate that phosphorylation of CENP-L and CENP-N controls CENP-LN complex formation and localization in a cell cycle-dependent manner. Mimicking constitutive phosphorylation of either CENP-L or CENP-N or simultaneously preventing phosphorylation of both proteins prevents CENP-LN localization and disrupts chromosome segregation. Our work suggests that cycles of phosphorylation and dephosphorylation are critical for CENP-LN complex recruitment and dynamics at kinetochores to enable cell cycle-dependent CCAN reorganization.

Incidence and Prevalence of Children's Diffuse Lung Disease in Spain.

BACKGROUND: Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain. METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019. RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47). CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury.

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Incidence and Prevalence of Children's Diffuse Lung Disease in Spain / Incidencia y prevalencia de las neumopatías intersticiales pediátricas en España

Background Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain. Methods Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019. Results A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28–10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81–51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2–18 years of age compared with children 0–2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47). Conclusions We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

Antecedentes Las neumopatías intersticiales pediátricas, también conocidas con el acrónimo chILD (del inglés children's Interstitial Lung Diseases), es un grupo heterogéneo de enfermedades raras con morbimortalidad relevante, cuyo diagnóstico y clasificación son complejos. Los estudios epidemiológicos son escasos. El objetivo de este trabajo fue analizar la incidencia y la prevalencia de chILD en España. Métodos Estudio prospectivo observacional multicéntrico en pacientes de 0 a 18 años afectos de chILD para analizar la incidencia y la prevalencia en España, a partir de datos recogidos en 2018 y 2019. Resultados Se recogieron 381 casos de chILD entre 51 unidades de neumología pediátrica de toda España, que cubrían el 91,7% de la población pediátrica. La incidencia promedio fue 8,18 (IC 95%: 6,28-10,48) casos nuevos/millón de niños por año. La prevalencia promedio fue de 46,53 (IC 95%: 41,81-51,62) casos/millón de niños. El grupo de edad con mayor prevalencia fue el de niños menores de un año. Se observaron diferentes entidades en niños de 2 a 18 años en comparación con niños de 0 a 2 años. Los diagnósticos más frecuentes fueron: glucogenosis intersticial pulmonar primaria en neonatos (17/65), hiperplasia de células neuroendocrinas en lactantes de uno a 12 meses (44/144), hemosiderosis pulmonar idiopática en niños de uno a 5 años (13/74), neumonía por hipersensibilidad en niños de 5 a 10 años (9/51) y esclerodermia en mayores de 10 años (8/47). Conclusiones Encontramos una mayor incidencia y prevalencia de chILD que las descritas previamente, probablemente debido a un mayor conocimiento y detección de estas enfermedades raras.

Differences between genetic dilated cardiomyopathy and myocarditis in children presenting with severe cardiac dysfunction.

Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0-16 years old) that presented with new-onset heart failure with left ventricle ejection fraction < 35% in whom we performed an endomyocardial biopsy (EMB) during the period from April 2007 to December 2020. The patients were classified into two groups: Group 1 included 18 patients with myocarditis. Group 2 included 9 patients with genetic cardiomyopathy. Findings favouring a diagnosis of myocarditis included a fulminant or acute presentation (77.8% vs 33.3%, p = 0.01), higher degree of cardiac enzyme elevation (p = 0.011), lower left ventricular dimension z-score (2.2 vs 5.4, p = 0.03) increase of ventricular wall thickness (88.8% vs 33.3%, p = 0.03) and oedema in the EMB. Seven (77.8%) patients with genetic cardiomyopathy had inflammation in the endomyocardial biopsy fulfilling the diagnostic criteria of inflammatory cardiomyopathy.Conclusion: Differentiating patients with a myocarditis from those with genetic cardiomyopathy can be challenging, even performing an EMB. Some patients with genetic cardiomyopathy fulfil the diagnostic criteria of inflammatory cardiomyopathy. Using invasive and non-invasive measures may be useful to develop a predictive model to differentiate myocarditis from genetic cardiomyopathy. What is Known: • Acute myocarditis could present with cardiogenic shock in paediatric patients. • Parvovirus B19 is the main cause of myocarditis in this population. What is New: • Current diagnostic criteria for myocarditis have limited use in paediatric patients presenting with new-onset heart failure. • Some patients with a genetic cardiomyopathy and a new-onset heart failure fulfill the diagnostic criteria of inflammatory cardiomyopathy.

Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise.

Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.

Kinetochore assembly throughout the cell cycle.

The kinetochore plays an essential role in facilitating chromosome segregation during cell division. This massive protein complex assembles onto the centromere of chromosomes and enables their attachment to spindle microtubules during mitosis. The kinetochore also functions as a signaling hub to regulate cell cycle progression, and is crucial to ensuring the fidelity of chromosome segregation. Despite the fact that kinetochores are large and robust molecular assemblies, they are also highly dynamic structures that undergo structural and organizational changes throughout the cell cycle. This review will highlight our current understanding of kinetochore structure and function, focusing on the dynamic processes that underlie kinetochore assembly.

Chromosome Segregation: Evolving a Plastic Chromosome-Microtubule Interface.

Despite a conserved requirement in mediating chromosome segregation, kinetochores display remarkable plasticity in their structure and composition. New work in holocentric insect species highlights the molecular rewiring that occurs when key structural components of the kinetochore are lost and centromere structure is changed.

A Venous Malformation: An Unusual Primary Cardiac Tumor in Children.

This case report describes a primary cardiac tumor, classified as venous malformation, diagnosed in an asymptomatic child. The tumor was located in the left atrium near the mitral valve without affecting the mitral valve's functioning. Complete resection of the lesion was performed because of the risk of systemic embolism. The lesion consisted of fibrous tissue with multiple venous vascular channels. The patient did not have similar lesions in other locations. Vascular primary cardiac tumors are extremely rare. Hemangiomas and lymphangiomas have been described previously, but to our knowledge, this is the first primary cardiac tumor identified as a venous malformation.

Isolated pulmonary interstitial glycogenosis associated with alveolar growth abnormalities: A long-term follow-up study.

INTRODUCTION: Pulmonary interstitial glycogenosis (PIG) is a rare infant interstitial lung disease characterized by an increase in the number of interstitial mesenchymal cells, presenting as enhanced cytoplasmic glycogen, and is considered to represent the expression of an underlying lung development disorder. METHODS: This study describes the clinical, radiological, and functional characteristics and long-term outcomes (median 12 years) of nine infants diagnosed with isolated PIG associated with alveolar simplification in the absence of other diseases. RESULTS: All patients presented with tachypnea. Additionally, seven patients had breathing difficulties and hypoxemia. Abnormalities in chest-computerized tomography (CT) with a pattern of ground-glass opacity, septal thickening, and air trapping were observed in all individuals, with images suggesting abnormal alveolar growth (parenchymal bands and architectural distortion). All lung biopsies showed alveolar simplification associated with an increased number of interstitial cells, which appeared as accumulated cytoplasmic glycogen. In the follow-up, all patients were asymptomatic. The respiratory function test was normal in only two patients. Five children showed an obstructive pattern, and two children showed a restrictive pattern. Chest-CT, performed after an average of 6.5 years since the initial investigation, revealed a partial improvement of the ground-glass opacity pattern; however, relevant alterations persisted. CONCLUSION: Although the patients with PIG in the absence of other associated pathologies had a good clinical outcome, significant radiographic alterations and sequelae in lung function were still observed after a median follow-up of 12 years, suggesting that PIG is a marker of some other persistent abnormalities in lung growth, which have effects beyond the symptomatic period.

Successful Treatment of Sinusitis by Acanthamoeba in a Pediatric Patient After Allogeneic Stem Cell Transplantation.

Acanthamoeba infections are rare and mostly occur in immunocompromised patients. Most of the reported cases after stem cell transplantation have been diagnosed postmortem. We present the case of a 3-year-old boy with chronic graft versus host disease post hematopoietic transplantation, who was successfully treated for Acanthamoeba.

The nucleus is a conserved mechanosensation and mechanoresponse organelle.

Cells in vivo exist in a dynamic environment where they experience variable mechanical influences. The precise mechanical environment influences cell-cell interactions, cell-extracellular matrix interactions, and in-turn, cell morphology and cell function. Therefore, the ability of each cell to constantly and rapidly alter their behavior in response to variations in their mechanical environment is essential for cell viability, development, and function. Mechanotransduction, the process by which mechanical force is translated into a biochemical signal to activate downstream cellular responses, is thus crucial to cell function during development and homeostasis. Although much research has focused on how protein complexes at the cell cortex respond to mechanical stress to initiate mechanotransduction, the nucleus has emerged as crucial to the ability of the cell to perceive and respond to changes in its mechanical environment. This additional method for mechanosensing allows for direct transmission of force through the cytoskeleton to the nucleus, which can increase the speed at which a cell changes its transcriptional profile. This review discusses recent work demonstrating the importance of the nucleus in mediating the cellular response to internal and external force, establishing the nucleus as an important mechanosensing organelle.

Raquitismo fetal mortal y celiaquía materna no diagnosticada / Fatal rickets in the fetus and undiagnosed maternal celiac disease

La enfermedad celíaca es una enteropatía frecuente que se asocia a manifestaciones clínicas muy variadas en parte debidas a la malabsorción. En la mujer se ha asociado a alteraciones obstétricas y ginecológicas como abortos de repetición, retraso intrauterino de crecimiento, parto prematuro y bajo peso al nacer. Presentamos el caso de una mujer con enfermedad celíaca no diagnosticada y con un parto eutócico de feto muerto de 34 semanas de gestación con alteraciones morfológicas graves de hipomineralización compatibles con raquitismo. En la literatura médica el raquitismo congénito secundario a malabsorción por enfermedad celíaca de la madre es excepcional. Se comentan los conocimientos actuales sobre el metabolismo fosfocálcico materno-fetal. Relacionamos la celiaquía activa con la hipocalcemia severa durante la gestación y con el raquitismo fetal mortal. Se sugiere la necesidad de un cribado de dicha enfermedad en las gestantes con signos de malabsorción o anomalías en el desarrollo del feto (AU)

Celiac disease is a relatively frequent enteropathy associated with a wide range of clinical manifestations, due in part to malabsorption. In women, it has been associated with obstetric and gynecological alterations such as repeated miscarriages, intrauterine growth delay, premature delivery, and low birth weight. We present the case of a woman with undiagnosed celiac disease who gave birth to a stillborn foetus via normal delivery after 34 weeks of gestation. The foetus presented severe morphological alterations due to hypomineralization which were compatible with rickets.In the medical literature congenital rickets secondary to maternal celiac disease due to malabsorption is rare. We discuss the current knowledge on maternofoetal phospho-calcium metabolism and relate active celiac disease with severe hypocalcaemia during pregnancy and fatal rickets in the foetus. We recommend screening for celiac disease in pregnant women with signs of malabsorption or impaired fetal development (AU)