Assessment of Quality of Life Using the Kidslife Scale in Individuals With Cornelia de Lange Syndrome.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a rare polymalformative genetic disorder with multisystemic involvement. Despite numerous clinical and molecular studies, the specific evaluation of the quality of life (QoL) and its relationship with syndrome-specific risk factors has not been explored. METHODS: The QoL of 33 individuals diagnosed with CdLS, aged between 4 and 21 years, was assessed using the Kidslife questionnaire. Specifically, the influence of 14 risk factors on overall QoL and 8 of its domains was analyzed. RESULTS: The study revealed below-median QoL (45.3 percentile), with the most affected domains being physical well-being, personal development, and self-determination. When classifying patients based on their QoL and affected domains, variants in the NIPBL gene, clinical scores ≥11, and severe behavioral and communication issues were found to be the main risk factors. CONCLUSIONS: We emphasize the need for a comprehensive approach to CdLS that encompasses clinical, molecular, psychosocial, and emotional aspects. The "Kidslife questionnaire" proved to be a useful tool for evaluating QoL, risk factors, and the effectiveness of implemented strategies. In this study, we underscore the importance of implementing corrective measures to improve the clinical score. Furthermore, we highlight the necessity of applying specific therapies for behavioral problems after ruling out underlying causes such as pain or gastroesophageal reflux and implementing measures that facilitate communication and promote social interaction.

Exploring kidney biopsy findings in congenital heart diseases: Insights beyond cyanotic nephropathy.

BACKGROUND: The association between congenital heart disease and chronic kidney disease is well known. Various mechanisms of kidney damage associated with congenital heart disease have been established. The etiology of kidneydisease has commonly been considered to be secondary to focal segmental glomerulosclerosis (FSGS), however, this has only been demonstrated in case reports and not in observational or clinical trials. AIM: To identify baseline and clinical characteristics, as well as the findings in kidney biopsies of patients with congenital heart disease in our hospital. METHODS: This is a retrospective observational study conducted at the Nephrology Department of the National Institute of Cardiology "Ignacio Chávez". All patients over 16 years old who underwent percutaneous kidney biopsy from January 2000 to January 2023 with congenital heart disease were included in the study. RESULTS: Ten patients with congenital heart disease and kidney biopsy were found. The average age was 29.00 years ± 15.87 years with pre-biopsy proteinuria of 6193 mg/24 h ± 6165 mg/24 h. The most common congenital heart disease was Fallot's tetralogy with 2 cases (20%) and ventricular septal defect with 2 (20%) cases. Among the 10 cases, one case of IgA nephropathy and one case of membranoproliferative glomerulonephritis associated with immune complexes were found, receiving specific treatment after histopathological diagnosis, delaying the initiation of kidney replacement therapy. Among remaining 8 cases (80%), one case of FSGS with perihilar variety was found, while the other 7 cases were non-specific FSGS. CONCLUSION: Determining the cause of chronic kidney disease can help in delaying the need for kidney replacement therapy. In 2 out of 10 patients in our study, interventions were performed, and initiation of kidney replacement therapy was delayed. Prospective studies are needed to determine the usefulness of kidney biopsy in patients with congenital heart disease.

Neurocognitive Function with Conventional Hemodialysis versus Post-Dilution Hemofiltration as Initial Treatment in ESKD Patients: A Randomized Controlled Trial - The DA-VINCI Study.

INTRODUCTION: The ideal modality choice and dialysis prescription during the first renal replacement therapy (RRT) session remain unclear. We conducted a pilot study to determine the safety risk for hemodialysis (HD) versus hemofiltration (HF) and its relationship with neurocognitive assessment on incident RRT patients. METHODS: Twenty-four incident RRT patients were included. Patients were randomized to the conventional HD group or post-dilution HF group. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA) tests were applied in all patients before and after session, and brain magnetic resonance image (MRI) was performed in 7 patients from the conventional HD group and 8 patients from the post-dilution HF group before and after the intervention. RESULTS: Baseline characteristics were similar between groups. Compared to conventional HD, post-dilution HF had longer treatment time. There were no significant changes in blood pressure after RRT in both groups. The MMSE test showed no significant differences between groups or within groups. The MOCA test showed an increase in the total score for the post-dilution HF group with no significant changes between groups. The MRI evaluation showed no differences between or within groups. CONCLUSION: Post-dilution HF is a safe alternative for the first HD session in incident RRT; it allows longer treatment time if ultrafiltration is required and has a similar neurological risk than conventional HD. This is a pilot study and that larger studies are needed to confirm the findings.

Urine Uromodulin, Kidney Tubulointerstitial Fibrosis, and Furosemide Response.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IFTA) are common findings on biopsy in chronic kidney disease (CKD) and strongly predictive of kidney failure. IFTA is poorly correlated with estimated glomerular filtration rate (eGFR) and albuminuria, the most common metrics of kidney disease. Thus, IFTA is prognostically important, yet its presence and severity are invisible to the clinician except when kidney biopsies are obtained. OBJECTIVES: To investigate 1) the cross-sectional association between urine uromodulin (uUMOD) and IFTA, and 2) to determine whether uUMOD levels were associated with diuretic response after a furosemide stress test. METHODS: We performed logistic regression to evaluate the association between uUMOD and fibrosis. We used linear regression models to assess the association of uUMOD with urine output. RESULTS: Among 52 participants, the mean age was 42 ± 16 years, 48% were women, 23% had diabetes, and the median eGFR was 56 ml/min/1.73m2. The mean uUMOD concentration was 5.1 (8.4) mcg/mL. Each halving of uUMOD was associated with 1.74 higher odds (95% CI 1.10, 2.75) of grade 2 or 3 fibrosis. However, this association was no longer significant after adjusting for baseline eGFR and albuminuria. Each halving of urine uromodulin was associated with a decreased response to furosemide. This association was also no longer significant after adjusting for baseline eGFR and albuminuria. CONCLUSION: In a population of individuals with a wide range of kidney function undergoing clinically indicated kidney biopsies, we did not find an association between uUMOD and interstitial fibrosis or response to loop diuretics after adjusting for eGFR and albuminuria.

Heart Disease Characterization and Myocardial Strain Analysis in Patients with PACS1 Neurodevelopmental Disorder.

BACKGROUND: PACS1 neurodevelopmental disorder (PACS1-NDD) (MIM# 615009) is a rare autosomal dominant disease characterized by neurodevelopmental delay, dysmorphic facial features, and congenital malformations. Heart disease (HD) is frequently present in individuals with PACS1-NDD, but a compressive review of these anomalies and an evaluation of cardiac function in a cohort of patients are lacking. METHODS: (i) Cardiac evaluation in 11 PACS1-NDD patients was conducted using conventional echocardiography. (ii) Heart function was assessed by tissue Doppler imaging, and two-dimensional speckle tracking was performed in seven patients and matched controls. (iii) This systematic review focused on determining HD prevalence in individuals with PACS1-NDD. RESULTS: In our cohort, 7 of 11 patients presented HD. (Among them, three cases of ascending aortic dilatation (AAD) were detected and one mitral valve prolapse (MVP).) None of the patients showed echocardiographic pathological values, and the left global longitudinal strain was not significantly different between patients and controls (patients -24.26 ± 5.89% vs. controls -20.19 ± 1.75%, p = 0.3176). In the literature review, almost 42% (42/100) of individuals with PACS1-NDD reportedly experienced HD. Septal defects were the most common malformation, followed by patent ductus arteriosus. CONCLUSIONS: Our results show a high prevalence of HD in PACS1-NDD patients; in this way, AAD and MVP are reported for the first time in this syndrome. Furthermore, a detailed cardiac function evaluation in our cohort did not reveal evidence of cardiac dysfunction in individuals with PACS1-NDD. Cardiology evaluation should be included for all individuals with Schuurs-Hoeijmakers syndrome.

Venous excess ultrasound score and acute kidney injury in patients with acute coronary syndrome.

AIMS: Systemic venous congestion is associated with an increased risk of acute kidney injury (AKI) in critically ill patients. Venous Excess Ultrasound Score (VExUS) has been proposed as a non-invasive score to assess systemic venous congestion. We aimed to evaluate the association between VExUS and AKI in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: This is a prospective study including patients with the diagnosis of ACS (both ST elevation and non-ST elevation ACS). VExUS was performed during the first 24 h of hospital stay. Patients were classified according to the presence of systemic congestion (VExUS 0/≥1). The primary objective of the study was to determine the occurrence of AKI, defined by KDIGO criteria. A total of 77 patients were included. After ultrasound assessment, 31 (40.2%) patients were categorized as VExUS ≥1. VExUS ≥1 was more frequently found in inferior vs. anterior myocardial infarction/non-ST-segment elevation acute myocardial infarction (48.3 vs. 25.8 and 22.5%, P = 0.031). At each increasing degree of VExUS, a higher proportion of patients developed AKI: VExUS = 0 (10.8%), VExUS = 1 (23.8%), VExUS = 2 (75.0%), and VExUS = 3 (100%; P < 0.001). A significant association between VExUS ≥1 and AKI was found [odds ratio (OR): 6.75, 95% confidence interval (CI): 2.21-23.7, P = 0.001]. After multivariable analysis, only VExUS ≥1 (OR: 6.15; 95% CI: 1.26-29.94, P = 0.02) remained significantly associated with AKI. CONCLUSION: In patients hospitalized with ACS, VExUS is associated with the occurrence of AKI. Further studies are needed to clarify the role of VExUS assessment in patients with ACS.

Unconventional OFF-ON Response of a Mono(calix[4]arene)-Substituted BODIPY Sensor for Hg2+ through Dimerization Reversion.

A new selective fluorogenic chemosensor for Hg2+, which combines a calixarene derivative with a BODIPY core as a fluorescent reporter, is described. The remarkable change in its fluorogenic properties in DMSO and CHCl3 has been analyzed. A study of its spectral properties on dilution, along with molecular modeling studies, allowed us to explain that this behavior involves the formation of a J-dimer, as well as how the sensing mechanism of Hg2+ proceeds.

Changes in the Inferior Vena Cava Are More Sensitive Than Venous Pressure During Fluid Removal: A Proof-of-Concept Study.

BACKGROUND: Congestion is central to the pathophysiology of heart failure (HF); thus, tracking congestion is crucial for the management of patients with HF. In this study we aimed to compare changes in inferior vena cava diameter (IVCD) with venous pressure following manipulation of volume status during ultrafiltration in patients with cardiac dysfunction. METHODS AND RESULTS: Patients with stable hemodialysis and with systolic or diastolic dysfunction were studied. Central venous pressure (CVP) and peripheral venous pressure (PVP) were measured before and after hemodialysis. IVCD and PVP were measured simultaneously just before dialysis, 3 times during dialysis and immediately after dialysis. Changes in IVCD and PVP were compared at each timepoint with ultrafiltration volumes. We analyzed 30 hemodialysis sessions from 20 patients. PVP was validated as a surrogate for CVP. Mean ultrafiltration volume was 2102 ± 667 mL. IVCD discriminated better ultrafiltration volumes ≤ 500 mL or ≤ 750 mL than PVP (AUC 0.80 vs 0.62, and 0.80 vs 0.56, respectively; both P< 0.01). IVCD appeared to track better ultrafiltration volume (P< 0.01) and hemoconcentration (P< 0.05) than PVP. Changes in IVCD were of greater magnitude than those of PVP (average change from predialysis: -58 ± 30% vs -28 ± 21%; P< 0.001). CONCLUSIONS: In patients undergoing ultrafiltration, changes in IVCD tracked changes in volume status better than venous pressure.

Colorimetric and fluorescent detection of synthetic cathinones in oral fluid with meso-aryl BODIPYs and Cu(ii).

Synthetic cathinones are a class of new psychoactive substances whose consumption has increased a lot and is widespread throughout the world. Thus, there is currently a need for rapid and simple detection of these drugs. In particular, detection of synthetic cathinones in oral fluid in drivers can be of great importance in preventing traffic accidents. Herein, we report two probes, based on BODIPY derivatives combined with Cu(ii), which are able to detect these drugs both in water and in oral fluid, by changes in color and fluorescence. The determined limits of detection for ephedrone (as a model drug) are lower than the usual concentrations in saliva after intake of this type of drug. The sensing mechanism seems to be related to the cathinone induced reduction of Cu(ii) to Cu(i) with concomitants changes in the BODIPY structure.

Subclinical myocardial dysfunction is revealed by speckle tracking echocardiography in patients with Cornelia de Lange syndrome.

This study assesses a possible cardiac dysfunction in individuals with Cornelia de Lange syndrome (CdLS) without diagnosed congenital heart disease (CHD) and its association with other factors. Twenty patients and 20 controls were included in the study divided into three age-dependent groups (A: < 10 yrs, B: 10-20 yrs, C: > 20 yrs), and were evaluated using conventional echocardiography, tissue doppler imaging (TDI), two-dimensional speckle tracking and genetic and biochemical analyses. The left ventricular global longitudinal strain (GLS) was altered (< 15.9%) in 55% of patients, being pathological in the older group (A: 19.7 ± 6.6; B: -17.2 ± 4.7; C: -13.6 ± 2.9). The speckle tracking technique revealed a downward trend in the values of strain, strain rate and velocity, especially in the oldest group. Likewise, the ejection fraction (LVEF) and shortening fraction (LVFS) values, although preserved, also showed a decreased with age (p < 0.05). The analytical markers of cardiovascular risk and cardiac function showed no alterations. The molecular analyses revealed 16 individuals carrying pathogenic variants in NIPBL, two with variants in SMC1A, one with a variant in RAD21 and one with a HDAC8 variant. This is the first systematic approach that demonstrates that individuals with CdLS may present early cardiomyopathy, which can be detected by speckle tracking technique even before the appearance of clinical symptoms and the alteration of other echocardiographic or analytical parameters. For all these reasons, cardiological followup is suggested even in the absence of CHD, especially from adolescence onwards.

Case report: A novel case of parental mosaicism in SMC1A gene causes inherited Cornelia de Lange syndrome.

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk.

Molecular Basis of the Schuurs-Hoeijmakers Syndrome: What We Know about the Gene and the PACS-1 Protein and Novel Therapeutic Approaches.

The Schuurs−Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins.

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient's phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.

Heteroditopic chemosensor to detect γ-hydroxybutyric acid (GHB) in soft drinks and alcoholic beverages.

Drug-Facilitated Sexual Assault (DFSA) is a problem of considerable dimensions on a global scale. Among the different compounds used in DFSA assaults, 4-hydroxybutyric acid (GHB) is one of the most elusive due to its physical and biological characteristics. Therefore, the development of real-time detection methods to detect GHB not only in drinks but also in urine is very important for personal and social security. Here, we report two new heteroditopic chemosensors capable of recognizing and detecting GHB in soft drinks, alcoholic beverages and synthetic urine. The compounds have two moieties: a trifluoroacetyl group and a thiourea, which are able to interact respectively with the hydroxyl and the carboxylic groups present in the GHB structure. In addition, the distance between these two groups has been optimized to allow a double interaction which guarantees the recognition even in very competitive media such as beverages or urine samples.

Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.

Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine.

A new hybrid organic-inorganic material for sensing spermine (Spm) and spermidine (Spd) has been prepared and characterized. The material is based on MCM-41 particles functionalized with an N-hydroxysuccinimide derivative and loaded with Rhodamine 6G. The cargo is kept inside the porous material due to the formation of a double layer of organic matter. The inner layer is covalently bound to the silica particles, while the external layer is formed through hydrogen and hydrophobic interactions. The limits of detection determined by fluorimetric titration are 27 µM and 45 µM for Spm and Spd, respectively. The sensor remains silent in the presence of other biologically important amines and is able to detect Spm and Spd in both aqueous solution and cells.

Intraocular Pressure Changes during Hemodiafiltration with Two different Concentrations of Sodium in the Dialysate.

Ocular complications are common among end-stage renal disease patients and some complications had been linked to increments of intraocular pressure (IOP) during hemodialysis. The changes of IOP during hemodiafiltration (HDF) have been scarcely investigated and the potential influence of the sodium dialysate concentration is unknown. The aim of this study was to compare the IOP changes during HDF with sodium dialysate concentration, either fixed or individualized. Thirteen end-stage renal disease patients participated in the study; they were treated with HDF using a dialysate sodium profile fixed at 138 mmol and another session with an individualized sodium profile. The intraocular pressure was measured before and after each session and every 30 min during HDF. Both groups had a similar HDF prescription, blood pressure, and biochemical parameters. At the end of hemodiafiltration, sodium concentration decreased only in the fixed sodium profile group. The number of patients with at least an episode of intraocular hypertension during HDF ranged from 5 (19%) to 8 (31%) without significant differences between right and left eye nor between dialysate sodium concentration. During HDF, there is a large variability of IOP; transient events of intraocular hypertension are highly prevalent in this sample, and they are not related to the sodium dialysate concentration.