Assessment of combined α-GAL enzyme activity and lyso-GL3 for Fabry disease screening in women with chronic kidney disease.

INTRODUCTION: The spectrum of clinical presentation of Fabry disease (FD) in women is broad and challenging. The aim is to evaluate the effectiveness of an alternative screening method for FD in women. METHODS: A collaborative multicenter cross-sectional study to evaluate the sensitivity and specificity of the combination of two tests (α-GAL enzyme activity assay and lyso-GL3 assay) for the diagnosis of FD in women. We included women with chronic kidney disease (CKD) stages 3 to 5, receiving conservative treatment or on dialysis programs, from different nephrology services in Brazil. RESULTS: We evaluated 1874 patients that underwent blood collection for α-GAL and lyso-GL3 assays. Isolated decreased α-GAL enzyme activity was found in 64 patients (3.5%), while isolated increased lyso-GL3 levels were found in 67 patients (3.6%), with one patient presenting alterations in both tests. All cases with low α-GAL enzyme activity and/or increased lyso-GL3 levels underwent genetic analysis for FD variants (132 performed GLA genetic test). Low α-GAL enzyme activity had higher sensitivity and specificity to detect FD compared to the other measures (elevated lyso-GL3 alone or both altered). The negative predictive value (NPV) of α-GAL activity was 99%, and the positive predictive value (PPV) was 9.2%. For lyso-GL3 assay, the specificity was 99.7% and the PPV was 2.9%, therefore considered inferior to α-GAL assay. Both assays altered, had higher PPV (100%) and higher NPV (99.7%) considered the best method. We found 7 cases of GLA gene variants found, resulting in an initial prevalence of 0.37% for FD in this sample female population. CONCLUSION: This study contributes to the diagnostic value of the biomarkers α-GAL and lyso-GL3 in the context of FD in women with CKD. The combination of these biomarkers was an effective approach for the diagnosis of the disease, with high PPV and NPV.

Sulforaphane Supplementation Did Not Modulate NRF2 and NF-kB mRNA Expressions in Hemodialysis Patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have reduced expression of erythroid nuclear factor-related factor 2 (NRF2) and increased nuclear factor κB (NF-κB). "Food as medicine" has been proposed as an adjuvant therapeutic alternative in modulating these factors. No studies have investigated the effects of sulforaphane (SFN) in cruciferous vegetables on the expression of these genes in patients with CKD. OBJECTIVE: The study aimed to evaluate the effects of SFN on the expression of NRF2 and NF-κB in patients on hemodialysis (HD). DESIGN AND METHODS: A randomized, double-blind, crossover study was performed on 30 patients on regular HD. Fourteen patients were randomly allocated to the intervention group (1 sachet/day of 2.5 g containing 1% SFN extract with 0.5% myrosinase) and 16 patients to the placebo group (1 sachet/day of 2.5 g containing corn starch colored with chlorophyll) for 2 months. After a washout period of 2 months, the groups were switched. NRF2 and NF-κB mRNA expression was evaluated by real-time quantitative polymerase chain reaction, and tumor necrosis factor alpha and interleukin-6 levels were quantified by enzyme-linked immunosorbent assay. Malondialdehyde was evaluated as a marker of lipid peroxidation. RESULTS: Twenty-five patients (17 women, 55 [interquartile range = 19] years and 55 [interquartile range = 74] months on HD) completed the study. There was no significant difference concerning the expression of mRNA NRF2 (P = .915) and mRNA NF-κB (P = .806) after supplementation with SFN. There was no difference in pro-inflammatory and oxidative stress biomarkers. CONCLUSION: 150 µmol of SFN for 2 months had no antioxidant and anti-inflammatory effect in patients with CKD undergoing HD.

Disease progression in Sanfilippo type B: Case series of Brazilian patients.

Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.

Protect the Kidneys and Save the Heart Using the Concept of Food as Medicine.

Chronic kidney disease is a significant risk factor for cardiovascular disease. In addition to traditional risk factors, such as hypertension, dyslipidemia, diabetes and smoking, patients with chronic kidney disease have a uremic phenotype marked by premature aging, mitochondrial dysfunction, persistent low-grade inflammation, gut dysbiosis and oxidative stress. These complications contribute to abnormal vascular and myocardial remodeling processes, resulting in accelerated vascular calcification, cellular and organ senescence and a high risk of cardiovascular disease. Nonpharmacological strategies, such as increasing physical activity and a healthy diet, may slow the progression of kidney disease and consequently protect the heart. Thus, a deep promotion and advocacy of nutritional guidance based on scientific data is needed. This narrative review discusses how nutritional interventions may delay progressive organ damage in the kidney-heart axis.

Sanfilippo syndrome type B: Analysis of patients diagnosed by the MPS Brazil Network.

Mucopolysaccharidosis type IIIB is a rare autosomal recessive disorder characterized by deficiency of the enzyme N-acetyl-alpha-d-glucosaminidase (NAGLU), caused by biallelic pathogenic variants in the NAGLU gene, which leads to storage of heparan sulfate and a series of clinical consequences which hallmark is neurodegeneration. In this study clinical, epidemiological, and biochemical data were obtained from MPS IIIB patients diagnosed from 2004-2019 by the MPS Brazil Network ("Rede MPS Brasil"), which was created with the goal to provide an easily accessible and comprehensive investigation of all MPS types. One hundred and ten MPS IIIB patients were diagnosed during this period. Mean age at diagnosis was 10.9 years. Patients were from all over Brazil, with a few from abroad, with a possible cluster of MPS IIIB identified in Ecuador. All patients had increased urinary levels of glycosaminoglycans and low NAGLU activity in blood. Main clinical symptoms reported at diagnosis were coarse facies and neurocognitive regression. The most common variant was p.Leu496Pro (30% of alleles). MPS IIIB seems to be relatively frequent in Brazil, but patients are diagnosed later than in other countries, and reasons for that probably include the limited awareness about the disease by health professionals and the difficulties to access diagnostic tests, factors that the MPS Brazil Network is trying to mitigate.

The magical smell and taste: Can coffee be good to patients with cardiometabolic disease?

Coffee is a beverage consumed globally. Although few studies have indicated adverse effects, it is typically a beneficial health-promoting agent in a range of diseases, including depression, diabetes, cardiovascular disease, and obesity. Coffee is rich in caffeine, antioxidants, and phenolic compounds, which can modulate the composition of the gut microbiota and mitigate both inflammation and oxidative stress, common features of the burden of lifestyle diseases. This review will discuss the possible benefits of coffee on complications present in patients with diabetes, cardiovascular disease and chronic kidney disease, outwith the social and emotional benefits attributed to caffeine consumption.

Archaea from the gut microbiota of humans: Could be linked to chronic diseases?

Archaea comprise a unique domain of organisms with distinct biochemical and genetic differences from bacteria. Methane-forming archaea, methanogens, constitute the predominant group of archaea in the human gut microbiota, with Methanobrevibacter smithii being the most prevalent. However, the effect of methanogenic archaea and their methane production on chronic disease remains controversial. As perturbation of the microbiota is a feature of chronic conditions, such as cardiovascular disease, neurodegenerative diseases and chronic kidney disease, assessing the influence of archaea could provide a new clue to mitigating adverse effects associated with dysbiosis. In this review, we will discuss the putative role of archaea in the gut microbiota in humans and the possible link to chronic diseases.

Health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism: Analysis of an international data set.

Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and - in acute diseases - metabolic decompensations nevertheless. Research on the subjective burden of IT-IEM remains sparse. Studies with appropriate sample sizes are needed to make valid statements about health-related quality of life (HrQoL) in children and adolescents with IT-IEM. Six international metabolic centres contributed self-reports and proxy reports of HrQoL (assessed with the Paediatric Quality of Life Inventory) to the final data set (n = 251 patients; age range 2.3-18.8 years). To compare HrQoL of the patient sample with norm data and between acute and non-acute IT-IEM, t tests were conducted. To examine the influence of child age, sex, diagnosis and current dietary treatment on HrQoL, multiple linear regression analyses were conducted. Self-reports and proxy reporst showed significantly lower HrQoL total scores for children with IT-IEM compared to healthy children. Current dietary treatment significantly predicted lower proxy reported total HrQoL. Children with non-acute IT-IEM reported significantly lower psychosocial health and emotional functioning than children with acute IT-IEM. The patient sample showed significantly impaired HrQoL and a diet regimen remains a risk factor for lower HrQoL. Differences in HrQoL between acute and non-acute IT-IEM subgroups indicate that factors beyond symptom severity determine the perception of disease burden. Identifying these factors is of crucial importance to develop and implement appropriate interventions for those in need.

Clinical oral profile of pediatric patients with atopic dermatitis: A cross-sectional study.

OBJECTIVES: This work aims to describe oral health conditions, eating habits, and oral hygiene in pediatric and adolescent patients with atopic dermatitis and correlate them with the severity of the Scoring Atopic Dermatitis (SCORAD). Also, we aim to estimate the effect of several variables on the diagnosis of dental caries in these patients. MATERIAL AND METHODS: A total of 92 children and adolescents with atopic dermatitis had their oral cavities examined. The effect of independent variables on the diagnosis of dental caries (outcome) was assessed using multiple binary logistic regression model. RESULTS: Mild patients presented higher score of decayed, missing, and filled teeth in permanent dentition than moderate patients (p = 0.040). In the multivariable regression final model, the covariates using inhaled corticoid (OR = 6.4; p = 0.003), type of teething [deciduous dentition (OR = 7.9; p = 0.027) and mixed dentition (OR = 10.5; p = 0.007)], and brushing quality [poor mechanical control (OR = 10.6; p < 0.0001)] demonstrated significant direct effect on the diagnosis of dental caries. CONCLUSIONS: Our findings suggest that the presence of dental biofilm, use of inhaled corticoid, and type of teething are related to the presence of caries in atopic dermatitis patients.

Health-related quality of life of Brazilian children and adolescents with benign and malignant solid tumours: A prospective cohort study during the first year after hospital admission.

INTRODUCTION: This study aims to assess the impact of paediatric benign and malignant solid tumours and its treatment on the health-related quality of life of children and adolescents who were followed up in a Reference Center in Pediatric Oncology in Rio de Janeiro. METHODS: It is a prospective cohort study. Quality of life assessment was performed using the PedsQL™ 4.0 Generic Core Scales and PedsQL™ 3.0 Cancer Module protocols three times: during hospital admission (T1), 6 months after admission (T2) and 1 year after admission (T3). RESULTS: We evaluated 132 patients, 59 men and 73 women, aged 2-17 years. In PedsQL™4.0, the Emotional Functioning scale was the one with the worst scores, while the scores on the Social Functioning scale was the best. In PedsQL™ 3.0, the worst domains were Procedural Anxiety and Worry. Patients with malignant bone tumours had the worst health-related quality of life. The group who received only surgery had better results. Total scores of PedsQL™4.0 and PedsQL™ 3.0 improved between T1 and T3. CONCLUSION: Children and adolescents with malignant and benign neoplasms undergo changes in quality of life as a result of the disease and treatment, but an improvement has been observed over time.

Behavioral and Emotional Problems in Early-Treated Brazilian Children and Adolescents with Phenylketonuria.

BACKGROUND Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene. When untreated, PKU leads to a significant intellectual deficiency. Although early initiation of dietary therapy allows normal cognitive development, low adherence to treatment may result in neuropsychological deficits, including attention problems. This study was performed to evaluate emotional and behavioral problems in early-treated children and adolescents with PKU using the Child Behavior Checklist - CBCL/6-18 answered by parents. MATERIAL AND METHODS The study included 36 PKU patients. The mean scores of internalizing, externalizing, and total problems, syndrome scales, and DSM-IV-oriented scales of patients were compared with those of controls. An analysis to evaluate the importance of adherence to treatment and presence of intellectual disability was also performed. RESULTS There were no significant differences between patients and controls for almost all CBCL/6-18 scales, with the exception of the Attention Problem Scale - CBCL-APS. The mean (±SD) of the CBCL-APS scores of patients (7.86±5.33) was considerably higher than the mean of the controls (6.07±4.37; p=0.016), but not different from the mean of a matched control subsample (6.69±4.46; p=0.316). The difference between the mean of the scores of DSM-IV/ADHD scale of patients (6.72±4.07) and controls (5.73±3.56; p=0.102) was not significant. Non-adherence to treatment and intellectual disability had a negative impact on both CBCL-APS and DSM-IV/ADHD scale scores. CONCLUSIONS Our findings indicate a significant prevalence of parents' complaints of attention problems and hyperactivity in non-adherent to treatment and intellectually low performing patients with PKU.

L-carnitine supplementation in the recovery of plasma L-carnitine in patients with heart failure submitted to coronary artery bypass grafting.

Coronary artery bypass grafting reduces plasma L-carnitine and may impair the production of myocardial energy. L-carnitine supplementation may elevate plasma L-carnitine and increase cardiac mechanical efficiency. The objective of this study was to verify the recovery of preoperative plasma LC in patients with heart failure undergoing coronary artery bypass grafting supplemented with a daily oral dose of 50 mg / kg. Volunteers with ischemic heart failure who underwent surgery were randomized into a supplemented group (A-received 50 mg / kg L-carnitine) or placebo group (B) for 60 days. Supplementation was started on the third postoperative day. The spectrophotometric enzymatic method was used to quantify plasma L-carnitine. In the preoperative period, both groups had plasma L-carnitine adequate to the reference range (18.9-71.1 µM). On the second postoperative day, there was a reduction in plasma L-carnitine in groups A (17.4%) and B (14.4%). In the comparison between the groups, plasma L-carnitine was higher in group A than B in 10º (p = 0.024), 30º (p = 0.001), and 60º postoperative day (p = 0.008). Supplementation of L-carnitine at a daily oral dose of 50 mg / kg in patients with heart failure undergoing coronary artery bypass grafting may recover preoperative plasma L-carnitine within 10 days.

Genetic Variability of Melipona subnitida (Hymenoptera: Apidae) in Introduced and Native Populations.

Melipona subnitida (Hymenoptera: Apidae) is a stingless bee native to Caatinga biome in Brazil, well adapted to hot and dry climate of that region and has been traditionally explored for honey production. Here, we evaluate the genetic structure of 173 colonies of M. subnitida in northeast Brazil by partially sequenced mitochondrial genes cytochrome oxidase I (COI) to compare an introduced population isolated for 30 yr into the Island of Fernando de Noronha (IFN) with the continental populations. We identified high haplotype diversity (0.8220) with 14 haplotypes on the continental populations, being three new ones, compared with the database GenBank. The haplotype H4 was present at the center of network, occurring in four localities on mainland and fixed as a single haplotype on IFN. We propose that the island populations originally introduced carried one haplotype (H4), even though IFN population is suffering pressure by island effect through changes on morphology. Studies on island populations could be a model to understand the dynamics of isolated populations and sustainable management of this biome to preserve M. subnitida.

Alopecia Areata-Part III: Prognosis and Treatment.

The prognosis of alopecia areata is better in cases with single and small lesions, and the variability of the extension of the disease is one of the criteria for the choice of treatment modality. Several medications have been described in the literature for the treatment of alopecia areata, including corticosteroids, minoxidil, and diphencyprone. The authors review treatments for alopecia areata.

Novel microduplications at Xp11.22 including HUWE1: clinical and molecular insights into these genomic rearrangements associated with intellectual disability.

Recently, we defined a minimal overlapping region for causal Xp11.22 copy number gains in males with intellectual disability (ID), and identified HECT, UBA and WWE domain-containing protein-1 (HUWE1) as the primary dosage-sensitive gene, whose overexpression leads to ID. In the present study, we used this minimal interval to search for HUWE1 copy number variations by quantitative polymerase chain reaction in a large cohort of Brazilian males with idiopathic ID. We detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. Breakpoint junction analysis showed a simple tandem duplication in the first patient, which has probably arisen by microhomology-mediated break-induced repair mechanism. In the second patient, the rearrangement is complex having an insertion of an intrachromosomal sequence at its junction. This kind of rearrangement has not been reported in Xp11.22 duplications and might have emerged by a replication- or recombination-based mechanism. Furthermore, the presence of infantile seizures in the second family suggests a potential role of increased KDM5C expression on epilepsy. Our findings highlight the importance of microduplications at Xp11.22 to ID, even in sporadic cases, and reveal new clinical and molecular insight into HUWE1 copy number gains.

Alopecia areata--Part II: diagnosis and pathology.

Alopecia areata is characterized by the abrupt appearance of round or oval, non-scarring, flat, single or multiple areas of alopecia, which may coalesce forming large patches of alopecia. The diagnosis is usually clinical but there are important differentials and dermatopathology may help in this definition.

Alopecia areata--Part I: Background .

Alopecia areata is a trichosis characterized by loss of hair, with the abrupt onset of round or oval, nonscarring, flat, single or multiple areas of alopecia lesions, which can coalesce. Several hypotheses have been raised to explain its etiology, with autoimmunity being accepted until today, along with genetic factors.

Pigment granule translocation in red ovarian chromatophores from the palaemonid shrimp Macrobrachium olfersi (Weigmann, 1836): functional roles for the cytoskeleton and its molecular motors.

The binding of red pigment concentrating hormone (RPCH) to membrane receptors in crustacean chromatophores triggers Ca²âº/cGMP signaling cascades that activate cytoskeletal motors, driving pigment granule translocation. We investigate the distributions of microfilaments and microtubules and their associated molecular motors, myosin and dynein, by confocal and transmission electron microscopy, evaluating a functional role for the cytoskeleton in pigment translocation using inhibitors of polymer turnover and motor activity in vitro. Microtubules occupy the chromatophore cell extensions whether the pigment granules are aggregated or dispersed. The inhibition of microtubule turnover by taxol induces pigment aggregation and inhibits re-dispersion. Phalloidin-FITC actin labeling, together with tannic acid fixation and ultrastructural analysis, reveals that microfilaments form networks associated with the pigment granules. Actin polymerization induced by jasplaquinolide strongly inhibits RPCH-induced aggregation, causes spontaneous pigment dispersion, and inhibits pigment re-dispersion. Inhibition of actin polymerization by latrunculin-A completely impedes pigment aggregation and re-dispersion. Confocal immunocytochemistry shows that non-muscle myosin II (NMMII) co-localizes mainly with pigment granules while blebbistatin inhibition of NMMII strongly reduces the RPCH response, also inducing spontaneous pigment dispersion. Myosin II and dynein also co-localize with the pigment granules. Inhibition of dynein ATPase by erythro-9-(2-hydroxy-3-nonyl) adenine induces aggregation, inhibits RPCH-triggered aggregation, and inhibits re-dispersion. Granule aggregation and dispersion depend mainly on microfilament integrity although microtubules may be involved. Both cytoskeletal polymers are functional only when subunit turnover is active. Myosin and dynein may be the molecular motors that drive pigment aggregation. These mechanisms of granule translocation in crustacean chromatophores share various features with those of vertebrate pigment cells.

Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network.

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.

Production of Toxins by the Gut Microbiota: The Role of Dietary Protein.

PURPOSE OF REVIEW: This narrative review will discuss how the intake of specific protein sources (animal and vegetable) providing specific amino acids can modulate the gut microbiota composition and generate toxins. A better understanding of these interactions could lead to more appropriate dietary recommendations to improve gut health and mitigate the risk of complications promoted by the toxic metabolites formed by the gut microbiota. RECENT FINDINGS: Gut microbiota is vital in maintaining human health by influencing immune function and key metabolic pathways. Under unfavorable conditions, the gut microbiota can produce excess toxins, which contribute to inflammation and the breakdown of the integrity of the intestinal barrier. Genetic and environmental factors influence gut microbiota diversity, with diet playing a crucial role. Emerging evidence indicates that the gut microbiota significantly metabolizes amino acids from dietary proteins, producing various metabolites with beneficial and harmful effects. Amino acids such as choline, betaine, l-carnitine, tyrosine, phenylalanine, and tryptophan can increase the production of uremic toxins when metabolized by intestinal bacteria. The type of food source that provides these amino acids affects the production of toxins. Plant-based diets and dietary fiber are associated with lower toxin formation than animal-based diets due to the high amino acid precursors in animal proteins.