Main oral characteristics and treatment of ligneous gingivitis and periodontitis in individuals with plasminogen deficiency: A systematic review.

OBJECTIVE: This systematic review evaluated the main clinical, radiographic, histopathological and treatment-related characteristics of ligneous gingivitis (LG) and periodontitis (LP) in individuals with plasminogen deficiency (PD). MATERIAL AND METHODS: Studies in humans diagnosed with PD, focusing on the evaluation of oral characteristics and treatment of the LG/LP were considered for inclusion criteria. Electronic searches were performed up to April 2024 in five databases and in the grey literature. Risk of bias was assessed according to the Joanna Briggs Institute Critical Appraisal Checklists for case reports. It was provided a narrative synthesis of the results. RESULTS: A total of 17 studies were included. All were case reports that analyzed 17 individuals with PD who presented with LG/LP. The relative frequency of PD type I was 56%, while type II constitutes the remaining 44%. In most studies, patients exhibited ulceration clinically, bone loss radiographically, and subepithelial eosinophilic material accumulation on histopathological evaluation. Conventional periodontal scaling was the most used management. All included studies provided well-described clinical characteristics and confirmed plasminogen deficiency through laboratory testing. Only three studies had a risk of bias values lower than 15%. CONCLUSIONS: Current evidence is limited and varied, complicating the diagnosis and treatment of GL/PL. Future studies should provide a more detailed account of treatments and include extended clinical and radiographic follow-up.

Increased ROS levels, antioxidant defense disturbances and bioenergetic disruption induced by thiosulfate administration in the brain of neonatal rats.

Sulfite oxidase deficiencies, either caused by deficiency of the apoenzyme or the molybdenum cofactor, and ethylmalonic encephalopathy are inherited disorders that impact sulfur metabolism. These patients present with severe neurodeterioration accompanied by cerebral cortex and cerebellum abnormalities, and high thiosulfate levels in plasma and tissues, including the brain. We aimed to clarify the mechanisms of such abnormalities, so we assessed the ex vivo effects of thiosulfate administration on energetic status and oxidative stress markers in cortical and cerebellar tissues of newborn rats. Thiosulfate (0.5 µmol/g) or PBS (vehicle) was injected into the fourth ventricle of rat pups. Thirty minutes after the injection, animals were euthanized and the brain structures were utilized for the experiments. Our data showed that thiosulfate decreased the reduced glutathione (GSH) concentrations, and superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) activities in the cortical structure. Thiosulfate also increased DCFH oxidation, hydrogen peroxide generation and glutathione reductase activity. In the cerebellum, thiosulfate reduced SOD and glutathione peroxidase activities but increased GST and CAT activities as well as DCFH oxidation. Regarding energy metabolism, thiosulfate specifically decreased complex IV activity in the cortex, whereas it increased cerebellar complex I and creatine kinase activities, indicating bioenergetic disturbances. The results suggest that the accumulation of thiosulfate causing redox disruption and bioenergetic alterations has a prominent role in the pathogenesis of sulfur metabolism deficiencies.

Dietary Intake of Micronutrients and Use of Vitamin and/or Mineral Supplements: Brazilian National Food Survey.

BACKGROUND/OBJECTIVES: Vitamin and/or mineral supplements are designed to correct micronutrient deficiencies or maintain adequate intake. However, evidence suggests the indiscriminate use of these products, particularly among populations that already meet their micronutrient requirements through diet. This study aims to estimate the prevalence of vitamin and/or mineral supplement use and assess the dietary intake of micronutrients among users and non-users in the Brazilian adult and elderly populations. METHODS: The prevalence of vitamin and/or mineral supplement use was estimated from a sample of 37,364 individuals who participated in the Brazilian National Food Survey, a module of the 2017-2018 Household Budget Survey. The average dietary intake of micronutrients-including calcium, magnesium, phosphorus, iron, copper, zinc, vitamin A, thiamine, riboflavin, niacin, cobalamin, pyridoxine, vitamin D, vitamin E, vitamin C, and folate-was calculated for both users and non-users of these supplements, based on 24 h dietary recalls collected during the survey. Analyses of dietary intake were stratified by sex and age group. RESULTS: The estimated overall prevalence of supplement use was 16.0% (95% CI: 15.4-16.6), with a higher prevalence among women (19.5% [95% CI: 18.7-20.5]) and the elderly (27.9% [95% CI: 26.4-29.4]). Women who used vitamin and/or mineral supplements showed higher average intakes for a greater number of dietary micronutrients compared to non-users. CONCLUSIONS: The findings from the analysis of average micronutrient intake from food sources, particularly among women and elderly women who used supplements, support the paradox of the "inverse supplement hypothesis", which suggests that individuals who use dietary supplements are often those with the least need for them.

Household Consumption of Adequately Iodized Salt: A Multi-Country Analysis of Socioeconomic Disparities.

BACKGROUND: Despite global efforts to promote universal salt iodization, iodine deficiency remains a public health issue in developing countries. OBJECTIVES: This study assessed the proportion and sociodemographic characteristics of households consuming adequately iodized salt in 49 low- and middle-income countries. METHODS: Data from DHS surveys of 49 low- and middle-income countries (2005-2021) were used to analyze household iodized salt prevalence. R version 4.0 was employed for statistical analyses. A random-effects meta-analysis was conducted to estimate overall and regional prevalence. RESULTS: We found that 83.4% of households consume adequately iodized salt, although with high heterogeneity (I2 = 100.0%). The East Asia and Pacific and the Europe and Central Asia regions showed high consumption rates of 87.6% and 87.7%, respectively, while Latin America and the Caribbean presented a significantly lower proportion of 30.8%. CONCLUSIONS: The study highlights the need for enhanced public health strategies to increase iodized salt consumption, especially in low-income and rural households. Addressing disparities in access, education, and affordability is crucial for improving iodine intake and preventing deficiency disorders, particularly among vulnerable populations like children and pregnant women.

Complement system component 3 deficiency modulates the phenotypic profile of murine macrophages.

The Complement System is composed of more than 40 proteins that act in innate and adaptive immunity. C3 is the most abundant one and C3-deficient patients are more susceptible to recurrent and severe infections. Several studies have demonstrated the importance of C3 in controlling infections. However, its role in leukocyte biology is still poorly understood. This study aimed to evaluate several cellular parameters in macrophages from C3-deficient mice and compare them to similar cells from wild-type counterparts. We observed that in the absence of C3, the population of F4/80low macrophages in the peritoneal cavity of thioglycolate-treated mice is diminished, probably due to the lack of chemotactic factors like C3a and low levels of C5a. Using fluorescence microscopy analysis, we observed that macrophages from C3-deficient mice exhibited morphological alterations when compared to similar cells from wild-type mice. We observed a significant increase in the expression of CD11c, which is part of CR4 (CD11c/CD18), in macrophages from C3-deficient compared to cells from wild-type mice. Treatment with 12-o-tetradecanoylphorbol-13-acetate, stimulated ROS production and MAPK activation by macrophages. However, these parameters were lower in macrophages from C3-deficient mice when compared to wild-type counterparts. In addition, the phagocytosis of iC3b-opsonized Zymosan particles was diminished in macrophages from C3-deficient mice. Our results suggest that C3 deficiency in C57Black/6 mice may influence specific morphological and functional parameters of macrophages, cells of fundamental importance for both the innate and acquired immune responses.

Impairment of neuromotor development and cognition associated with histopathological and neurochemical abnormalities in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase deficient mice.

Patients with glutaric acidemia type I (GA I) manifest motor and intellectual disabilities whose pathogenesis has been so far poorly explored. Therefore, we evaluated neuromotor and cognitive abilities, as well as histopathological and immunohistochemical features in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase (GCDH) deficient knockout mice (Gcdh-/-), a well-recognized model of GA I. The effects of a single intracerebroventricular glutaric acid (GA) injection in one-day-old pups on the same neurobehavioral and histopathological/immunohistochemical endpoints were also investigated. Seven-day-old Gcdh-/- mice presented altered gait, whereas those receiving a GA neonatal administration manifested other sensorimotor deficits, including an abnormal response to negative geotaxis, cliff aversion and righting reflex, and muscle tone impairment. Compared to the WT mice, adult Gcdh-/- mice exhibited motor impairment, evidenced by poor performance in the Rota-rod test. Furthermore, neonatal GA administration provoked long-standing short- and long-term memory impairment in adult Gcdh-/- mice. Regarding the histopathological features, a significant increase in vacuoles and neurodegenerative cells was observed in both the cerebral cortex and striatum of 15- and 60-day-old Gcdh-/- mice and was more pronounced in mice injected with GA. Neuronal loss (decrease of NeuN staining) was also significantly increased in the cerebral cortex and striatum of Gcdh-/- mice, particularly in those neonatally injected with GA. In contrast, immunohistochemistry of MBP, astrocytic proteins GFAP and S100B, and the microglial marker Iba1 was not changed in 60-day-old Gcdh-/- mice, suggesting no myelination disturbance, reactive astrogliosis, and microglia activation, respectively. These data highlight the neurotoxicity of GA and the importance of early treatment aiming to decrease GA accumulation at early stages of development to prevent brain damage and learning/memory disabilities in GA I patients.

Effect of Oral Zinc Supplementation on Phase Angle and Bioelectrical Impedance Vector Analysis in Duchenne Muscular Dystrophy: A Non-Randomized Clinical Trial.

Zinc plays a crucial role in cell structure and functionality. Neurodegenerative Duchenne muscular dystrophy (DMD) alters muscle membrane structure, leading to a loss of muscle mass and strength. The objective of this study was to evaluate the changes in phase angle (PA) and bioelectrical impedance vector analysis (BIVA) results in patients with DMD after oral zinc supplementation. This clinical trial included 33 boys aged 5.6 to 24.5 years diagnosed with DMD. They were divided into three groups according to age (G1, G2, and G3) and supplemented with oral zinc. The mean serum zinc concentration was 74 µg/dL, and 29% of patients had concentrations below the reference value. The baseline values (mean (standard deviation)) of the bioelectrical impedance parameters PA, resistance (R), and reactance (Xc) were 2.59° (0.84°), 924.36 (212.31) Ω, and 39.64 (8.41) Ω, respectively. An increase in R and a decrease in PA and lean mass proportional to age were observed, along with a negative correlation (r = -0.614; p < 0.001) between age and PA. The average cell mass in G1 was greater than that in G3 (p = 0.012). There were no significant differences in serum zinc levels or bioelectrical impedance parameters before and after zinc supplementation. We conclude that this population is at risk of zinc deficiency and the proposed dosage of zinc supplementation was not sufficient to alter serum zinc levels, PA and BIVA results.

Impact of 5-Lipoxygenase Deficiency on Dopamine-Mediated Behavioral Responses.

The 5-lipoxygenase/leukotriene system has been implicated in both physiological and pathological states within the central nervous system. Understanding how this system interacts with the dopaminergic system could provide valuable insights into dopamine-related pathologies. This study focused on examining both motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotriene-deficient mice. We used pharmacological agents such as amphetamine, apomorphine, and reserpine to challenge the dopaminergic system, evaluating their effects on prepulse inhibition reaction (PPI), general motor activity, and oral involuntary movements. Additionally, we analyzed striatal glial marker expression (GFAP and Iba-1) in reserpine-treated mice. The 5-lipoxygenase/leukotriene-deficient mice exhibited increased spontaneous locomotor activity, including both horizontal and vertical exploration, along with stereotyped behavior compared to wild-type mice. This hyperactivity was reduced by acute apomorphine treatment. Although basal PPI responses were unchanged, 5-lipoxygenase/leukotriene-deficient mice displayed a significant reduction in susceptibility to amphetamine-induced PPI disruption. Conversely, these mice were more vulnerable to reserpine-induced involuntary movements. There were no significant differences in the basal expression of striatal GFAP and Iba-1 positive cells between 5-lipoxygenase/leukotriene-deficient and wild-type mice. However, reserpine treatment significantly increased GFAP immunoreactivity in wild-type mice, an effect not observed in 5-lipoxygenase-deficient mice. Additionally, the percentage of activated microglia was significantly higher in reserpine-treated wild-type mice, an effect absents in 5-lipoxygenase/leukotriene-deficient mice. Our findings suggest that 5-lipoxygenase/leukotriene deficiency leads to a distinctive dopaminergic phenotype, indicating that leukotrienes may influence the modulation of dopamine-mediated responses.

A History of the Elimination of Iodine Deficiency Disorders in the Americas: A Dramatic Achievement and Lessons Learned.

Iodine is essential for the synthesis of thyroid hormones, which regulate cell metabolism, growth, and development. Although iodine deficiency (ID) causes adverse health effects across the lifespan, it is particularly problematic in pregnancy, when it can lead to irreversible fetal brain damage. A high prevalence of severe ID, manifesting as endemic goiter and cretinism, predated the arrival of European explorers in the Americas. Early 20th century surveys showed that most countries in the Western Hemisphere had regions with a goiter prevalence >50%. In North America, the introduction of iodized salt led to the elimination of ID by the 1950s. Although most Latin American countries passed laws mandating salt iodization in the 1950s-1960s, initial programs met with limited success because laws were unenforced, monitoring was absent, and the importance of iodine nutrition was inadequately communicated. A renewed interest in ID prevention arose in the 1970s-1980s, when 3 Andean countries were the first in Latin America to implement effective salt iodization programs. Over the last 3 decades there has been a stronger political commitment to ID prevention across the region, alignment with the broader nutrition and development agenda, and a widespread recognition of optimal iodine nutrition as a fundamental human right. Currently, 92% of households in Latin America consume adequately iodized salt, and urinary iodine concentrations in schoolchildren reflect optimal iodine nutrition across the region. However, additional work remains. It is essential to ensure ongoing government commitment; to monitor population iodine status and the production, quality, and household consumption of iodized salt; and to maintain advocacy and communication strategies. Universal salt iodization programs must be harmonized with efforts to reduce salt intake for cardiovascular disease prevention. Ensuring optimal iodine nutrition in pregnant women, who may remain deficient even when intakes in schoolchildren are optimized, requires particular attention.

Gly183Ser homozygous mutation of the steroid 5-a reductase type 2 (SRD5A2) gene in a Brazilian patient: case report.

OBJECTIVES: Steroid 5α-reductase type 2 deficiency (5α-RD2) is an autosomal recessive disorder caused by mutations in the SRD5A2 gene. This condition is characterized by reduced enzymatic activity of the 5α-reductase type 2 enzyme. Individuals with mutations in the SRD5A2 gene may exhibit various symptoms of under-masculinization in 46, XY individuals. We conducted a comprehensive analysis of the SRD5A2 gene in a patient with disorder of sex development (DSD). CASE PRESENTATION: We describe a patient with a homozygous Gly183Ser variant in the SRD5A2 gene. Their sibling also carries this variant in homozygosity, while both parents have it in a heterozygous state. The patient presents with predominantly female traits and was raised as a girl. Although the siblings exhibit distinct phenotypic characteristics, both have assumed a male gender identity. CONCLUSIONS: This study reveals different phenotypes for the two siblings, highlighting the complexity of establishing a genotype-phenotype correlation in the SRD5A2 gene. It is noteworthy that the Gly183Ser variant seems to be more prevalent among individuals of African descent, aligning with our patient's ethnic background.

Rare primary vasculitis: update on multiple complex diseases and the new kids on the block.

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

Absence of TNFR1 promotes a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with a wide spectrum of cognitive deficits, motor impairment, and psychiatric disturbances resulting from liver damage. The cytokine TNF has been considered the main cytokine in the development and progression of HE, with a pivotal role in the initiation and amplification of the inflammatory cascade. The aim of the present study was to evaluate the involvement of TNF type 1 receptor (TNFR1) in locomotor deficits and in the levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70, CCL2, CX3CL1 and BDNF from the frontal cortex and hippocampus of TNFR1 knockout mice (TNFR1-/-) mice with HE induced by thioacetamide. Wild-type (WT) animals with HE developed locomotor deficit. The absence of TNFR1 absence of TNFR1 in HE animals attenuated the locomotor activity impairment in parallel with a balanced neuroinflammatory environment 24 h after the administration of thioacetamide. Taken together, the data suggests that the absence of TNFR1 promoted a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice.

Tannic acid: A possible therapeutic agent for hypermethioninemia-induced neurochemical changes in young rats.

This study explores the therapeutic benefits of tannic acid (TnA) in an experimental protocol of chronic hypermethioninemia in rats. Rats were categorized into four groups: Group I - control, Group II - TnA 30 mg/kg, Group III - methionine (Met) 0.2-0.4 g/kg + methionine sulfoxide (MS) 0.05-0.1 g/kg, Group IV - TnA/Met + MS. Saline was administered by subcutaneous pathway into groups I and II twice daily from postnatal day 6 (P6) to P28, whereas those in groups III and IV received Met + MS. From P28 to P35, groups II and IV received TnA orally. Animals from group III presented cognitive and memory impairment assessed through object recognition and Y-maze tests (p < 0.05). Elevated levels of reactive species, lipid peroxidation, and nitrites followed by a decline in sulfhydryl content, catalase activity, and superoxide dismutase activity were observed in animals treated with Met + MS (p < 0.05). However, TnA treatment reversed all these effects (p < 0.05). In group III, there was an increase in acetylcholinesterase activity and IL-6 levels, coupled with a reduction in Na+/K+-ATPase activity (p < 0.05). TnA was able to protect against these effects (p < 0.05). The gene expression of catalase, brain-derived neurotrophic factor, and nuclear factor erythroid 2-related factor 2 was decreased in the hippocampus and striatum from group III (p < 0.05). TnA reversed almost all of these alterations (p < 0.05). These findings suggest that TnA is a therapeutic target for patients with hypermethioninemia.

Goiter, iodine bioavailability and intrauterine growth restriction in Indigenous and Afro-descendant pregnant women from six non-metropolitan areas of Colombia (2019-2020).

INTRODUCTION: Iodine is an essential mineral for fetal growth and brain development. The aim of this research was to evaluate goiter, iodine deficiency and intrauterine growth restriction in pregnant women of minority ethnic groups in Colombia. METHODS: A cross-sectional study was performed in six non-metropolitan areas of Colombia. RESULTS: A total of 318 Indigenous and Afro-descendant pregnant women were invited to participate: 248 (83.2%) Indigenous and 50 (16.8%) Afro-descendants were studied. The mean age was 24 years (range 13-44 years). Of the women, 130 (43.5%) were from the department of Cauca, 72 (24.1%) were from Córdoba, 28 (9.4%) were from Guajira, 26 (8.8%) were from Sierra Nevada de Santa Marta, 22 (7.4%) were from Amazonas, 16 (5.4%) were from Meta and 4 (1.3%) were from the department of Cesar. A total of 244 (81.8%) were illiterate and 291 (97.7%) were of very low socioeconomic level. Goiter was observed in 69 (23.3%) pregnant women (38 (41.7%) from the department of Cauca, 10 (35.7%) from Guajira, 5 (31.2%) from Meta, 6 (27.2%) from Amazonas and 10 (13.8%) from Córdoba). Iodine deficiency (<100 µg/L) was observed in 42 (14.9%) pregnant women (16 (11.6%) mild (50-99 µg/L), 19 (13.8%) moderate (20-49 µg/L) and 7 (5.1%) severe (<20 µg/L)). Being literate was a protective factor for iodine deficiency (odds ratio (OR)=0.19, 95% confidence interval (CI) 0.04-0.84, p=0.016). Being illiterate and iodine deficient was only a risk factor for goiter (OR=6.72, 95%CI 3.9-9.5, p=0.038) in the department of Cauca. CONCLUSION: A high prevalence of goiter, iodine deficiency and intrauterine growth restriction was observed in minority ethnic groups of Colombia. The highest prevalence and risk was observed in the department of Cauca.

Micronutrient Consumption Among Postpartum Women and Food Insecurity.

This study aimed to assess the prevalence of inadequate micronutrient intake and its risk factors among women one year after giving birth. 240 women of reproductive age were assessed. Micronutrient intake was assessed from two 24-hour records at three stages (3-6-12 months after childbirth). A generalized linear mixed-effect model was used to assess the factors associated with food intake. A prevalence of inadequate micronutrient intake was observed, with the exception of iron. Intake was lower among food-insecure women (zinc: ß -0.13; iron: ß -0.09; vitamin C: ß -0.44). The postpartum period and food insecurity remained statistically associated with lower food consumption in the explanatory models tested.

Neu1 deficiency and fibrotic lymph node microenvironment lead to imbalance in M1/M2 macrophage polarization.

Macrophages play a pivotal role in tissue homeostasis, pathogen defense, and inflammation resolution. M1 and M2 macrophage phenotypes represent two faces in a spectrum of responses to microenvironmental changes, crucial in both physiological and pathological conditions. Neuraminidase 1 (Neu1), a lysosomal and cell surface sialidase responsible for removing terminal sialic acid residues from glycoconjugates, modulates several macrophage functions, including phagocytosis and Toll-like receptor (TLR) signaling. Current evidence suggests that Neu1 expression influences M1/M2 macrophage phenotype alterations in the context of cardiovascular diseases, indicating a potential role for Neu1 in macrophage polarization. For this reason, we investigated the impact of Neu1 deficiency on macrophage polarization in vitro and in vivo. Using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages from Neu1 knockout (Neu1-/- ) mice and wild-type (WT) littermate controls, we demonstrated that Neu1-deficient macrophages exhibit an aberrant M2-like phenotype, characterized by elevated macrophage mannose receptor 1 (MMR/CD206) expression and reduced responsiveness to M1 stimuli. This M2-like phenotype was also observed in vivo in peritoneal and splenic macrophages. However, lymph node (LN) macrophages from Neu1-/- mice exhibited phenotypic alterations with reduced CD206 expression. Further analysis revealed that peripheral LNs from Neu1-/- mice were highly fibrotic, with overexpression of transforming growth factor-beta 1 (TGF-ß1) and hyperactivated TGF-ß signaling in LN macrophages. Consistently, TGF-ß1 was found to alter M1/M2 macrophage polarization in vitro. Our findings showed that Neu1 deficiency prompts macrophages towards an M2 phenotype and that microenvironmental changes, particularly increased TGF-ß1 in fibrotic tissues such as peripheral LNs in Neu1-/- mice, further influence M1/M2 macrophage polarization, highlighting its sensitivity to the local microenvironment. Therapeutic interventions targeting Neu1 or TGF-ß signaling pathways may offer the potential to regulate macrophage behavior across different diseases.

Magnesium, selenium and zinc deficiency compromises antioxidant defense in women with obesity.

Studies have shown that deficiencies in magnesium, selenium, and zinc in individuals with obesity compromise the endogenous antioxidant defense system. This study aimed to evaluate the impact of mineral deficiency on enzymatic antioxidant defense in women with obesity. The study involved 63 women with obesity (BMI ≥ 35 kg/m2) and 77 eutrophic women (BMI between 18.5 and 24.9 kg/m2). Variables such as fasting glucose, glycated hemoglobin, fasting insulin, and serum lipids were analyzed. Insulin resistance was measured using the homeostasis assessment model (HOMA-IR) and beta cell function using the homeostasis assessment model (HOMA-ß). Dietary intake of energy, macronutrients (including magnesium, zinc, and selenium), and plasma, erythrocyte, and urinary concentrations of these minerals were measured and analyzed. Serum cortisol, plasma leptin, plasma thiobarbituric acid reactive substances, and the activity of erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPX), and erythrocyte catalase were also analyzed. Women with obesity had reduced plasma and erythrocyte concentrations and greater urinary excretion of all minerals compared to normal weight women (p < 0.05). There was a positive association between erythrocyte concentrations of zinc and selenium and the activity of the GPX and SOD enzymes in erythrocytes in women with obesity (p < 0.05), in addition to a positive association between serum insulin and the enzyme GPX, which is dependent on dietary selenium (p < 0.05). Individuals with obesity are deficient in magnesium, selenium, and zinc, which appears to impair the antioxidant defense system and contribute to important metabolic disorders such as oxidative stress in these patients.

Tuberculosis in otherwise healthy adults with inherited TNF deficiency.

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.

Evaluation of 73 Enlisted Patients for Liver Transplant with Unknown Etiology Reveals a Late-Diagnosed Case of Lysosomal Acid Lipase Deficiency.

Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP-Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients.

Cerebral White Matter Alterations Associated With Oligodendrocyte Vulnerability in Organic Acidurias: Insights in Glutaric Aciduria Type I.

The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.