Maternal Steroid Hormone Levels in Early Pregnancy and Autism in the Offspring: A Population-Based, Nested Case-Control Study.

BACKGROUND: A role for prenatal steroid hormones in the etiology of autism has been proposed, but evidence is conflicting. METHODS: Here, we examined serum levels of maternal estradiol, testosterone, 17-hydroxyprogesterone (OHP), and cortisol from the first trimester of gestation (mean = 10.1 weeks) in relation to the odds of diagnosed autism with and without co-occurring intellectual disability (ID) in the offspring (n = 118 autism with ID, n = 249 autism without ID, n = 477 control). Levels of maternal hormones were measured using highly sensitive liquid chromatography tandem mass spectrometry, standardized according to gestational timing of sample collection, and analyzed with restricted cubic spline logistic regression models adjusting for child's sex and maternal health, demographic, and socioeconomic factors. RESULTS: We observed significant nonlinear associations between maternal estradiol, 17-OHP, and cortisol with autism, which varied with the presence of co-occurring ID. Compared to mean levels, lower levels of estradiol were associated with higher odds of autism with ID (odds ratio for concentrations 1 SD below the mean = 1.66; 95% CI, 1.24-2.11), while higher cortisol levels were associated with lower odds (odds ratio for 1 SD above the mean = 0.55; 95% CI, 0.36-0.88). In contrast, higher 17-OHP was associated with increased odds of autism without ID (odds ratio for 1 SD above the mean = 1.49; 95% CI, 1.11-1.99). We observed no evidence for interaction with sex of the child. CONCLUSIONS: These findings support the notion that the maternal steroid hormonal environment in early pregnancy may contribute to autism, but also emphasize the complex relationship between early-life steroid exposure and autism.

Primary Intraosseous Granular Cell Tumor of the Sphenoid and Central Skull Base in a Pediatric Patient.

BACKGROUND: Granular cell tumors occur in all ages and many anatomic sites. In the craniofacial region, they typically arise in soft tissue, not bone. We present a primary intra-osseous granular cell tumor of the sphenoid and central skull base arising in a 12- year- old girl. CASE REPORT: A 12-year-old female with sickle cell disease and Jeavons syndrome presented with seizures. Imaging and partial resection revealed an expansile benign granular cell tumor (GCT) involving the sphenoid body, pterygoid process, and central skull base. The disease has remained stable after 36-month follow up. DISCUSSION: GCT primarily involving the osseous sphenoid/skull base has not been previously reported in a child. Although mostly benign, some are aggressive, with malignant transformation in 1-2%. Surgery is the mainstay of treatment, but in the skull base this may be limited by adjacent critical structures. Decision-making is guided by anatomic extent, histology, and clinical behavior.

Preoperative Transfusion in Sickle Cell Disease Children Undergoing Adenotonsillectomy.

Objective: To perform a systematic review and meta-analysis comparing two pre-operative transfusion regimens (conservative versus aggressive) in children with sickle cell disease(SCD) undergoing adenotonsillectomy in terms of post-operative complications, complications related to SCD and transfusion related complications. Data Sources and Review Methods: A literature review was performed through PubMed, EMBASE, Cochrane, and Ovid databases using the following phrases: (Adenotonsillectomy OR Tonsillectomy) AND (Sickle Cell Disease OR Sickle Cell Trait). Using predetermined inclusion and exclusion criteria, seven articles were selected for systemic review and two control trials were included in meta-analysis. Results: Out of a total of 3,146 results, seven articles were selected for review and two controlled trials were included in the meta-analysis. There was no statistically significant difference in the rate of primary and secondary hemorrhage between the aggressive and conservative transfusion regimens (RR = 3.1, CI = 0.84-11.4, p-value = 0.089). The rate of sickle cell disease related complications including vaso-occlusive crisis and acute chest syndrome was also not statistically significant between the two transfusion groups (RR = 1.4, CI = 0.7-2.8, p-value = 0.339). Even though, the transfusion related complications did not reach statistical significance, there was a higher complication rate in the group receiving aggressive blood transfusion. Conclusion: In SCD children undergoing adenotonsillectomy, an aggressive transfusion regimen that focuses on reducing the Hemoglobin S ratio to below 30% has not been shown to be more effective in reducing post-operative complications when compared to a conservative transfusion regimen. Therefore, it is reasonable to utilize a conservative transfusion regimen, thereby reducing the transfusion-associated risks.

Autoimmune Myelofibrosis in a 12-Year-old Male With Monosomy 7, Systemic Lupus Erythematous and Lupus Nephritis: A Case Report and Review of the Literature.

Complete or partial loss of chromosome 7 is a common and well-known cytogenetic abnormality associated with preleukemic myelodysplasia and myeloid leukemia but not with autoimmune myelofibrosis. Detection of this molecular change represents poor prognosis. When malignant transformation occurs, the condition tends to be chemotherapy-resistant requiring haematopoietic stem cell transplantation (HSCT) to obtain a cure. Disappearance after immunosuppressive therapy has been documented in children with hematological disorders but not in association with cyclophosphamide and systemic lupus erythematous.We present the interesting case of a 12-year-old male with monosomy 7, systemic lupus erythematous, and lupus nephritis with the resolution of the monosomy 7 and autoimmune myelofibrosis after treatment with cyclophosphamide, along with a review of the literature.

Multisystem Inflammatory Syndrome in a Pediatric Patient With Sickle Cell Disease and COVID-19: A Case Report.

To this day, there are limited data about the effects and management of coronavirus disease infection in pediatric patients with sickle cell disease. We present the management and successful clinical course of an 8-year-old female with homozygous sickle cell disease (SS) and severe acute chest syndrome secondary to coronavirus disease 2019 infection, complicated by cortical vein thrombosis.

Sickle Cell Disease: Advances in Treatment.

BACKGROUND: Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases. METHODS: This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease. RESULTS: Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available. These agents have the potential to improve survival and quality of life for individuals with sickle cell disease. Also discussed is stem cell transplantation that, to date, is the only curative approach for this disease, as well as the current status of gene therapy. CONCLUSION: These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Although interest in sickle cell research has blossomed, many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past.

Impact of Hurricane Katrina on healthcare delivery for New Orleans patients, 2005-2014.

BACKGROUND AND OBJECTIVES: Hematology/oncology patients have special health needs. To identify barriers to care, we surveyed patients/parents at Children's Hospital of New Orleans 1 year after Hurricane Katrina. We then implemented a "Hurricane Action Plan"-identification of families' evacuation plans at each hurricane season's onset; of hospital(s) and pharmacies in the intended evacuation area; updating roadmaps/treatment plans; giving information to families requiring hematology/oncology services in evacuation areas. Administration of a second survey was initiated 7 years post Katrina to assess the efficacy of the "Hurricane Action Plan." METHODS: Both surveys were conducted on random patients attending Children's Hospital. Survey #1 was performed in 2006, while survey #2 was conducted in 2013-2014. RESULTS: Eighty-nine percent of 124 families left New Orleans during Hurricane Katrina; only 50% had an evacuation plan. Twenty-five percent of families had difficulty physically accessing care; others (13%) could not find a hematology/oncology provider for follow-up and had difficulty reaching their primary provider or making appointments. An additional 25 percent did not have access to medical records. There was no access to mental health services. Eighty- two patients/representatives were surveyed in 2013/2014; 72% of families were evacuated during subsequent hurricane seasons with 78% of families having an evacuation plan. Thirty-six percent of patients had a roadmap/treatment plan with them; 71% had a 2-week medication supply. Ninety-two percent found information given to them by providers helpful. CONCLUSIONS: Interventions instituted to allow greater access to care by our hematology/oncology patients after Hurricane Katrina resulted in better preparedness, easier acquisition of information, and possibly better continuity of care.

Sickle Cell Disease is Associated With Elevated Levels of Skin Advanced Glycation Endproducts.

Sickle cell disease (SCD) is associated with increased oxidative stress which potentially enhances generation of advanced glycation endproducts (AGEs). We estimated skin accumulation of AGEs in SCD patients and assessed their relationship with hemolysis and nephropathy. Skin intrinsic fluorescence (SIF), an estimate of AGEs, was assessed in African American patients with and without SCD. After skin excitation with light at 375, 405, and 420 nm, raw autofluorescence was adjusted using specific intrinsic corrections. Group differences in SIF were evaluated by multiple variable regression using chronological age and sex as covariates. The relationship of SIF with reticulocyte count, serum lactate dehydrogenase, estimated glomerular filtration rate (GFR), plasma creatinine, bilirubin, and urine microalbumin was assessed. There were 48 SCD patients (29 male/19 female, age=13.4±3.6 y) and 51 controls (25 male/26 female, age=10.4±5.0 y). SIF375(1.0,0.0), SIF405(0.5,0.5), and SIF420(0.5,0.5) were significantly higher in SCD patients. There was no difference in SIF between SCD patients with and without microalbuminuria. SIF 420(0.5,0.5) was correlated with reticulocyte count (r=0.33; P=0.03). Skin AGEs as estimated by SIF were higher in children with SCD and weakly associated with 1 measure of hemolysis. Further study is needed to determine whether chronic increased deposition of AGEs is associated with development of complications of SCD.

A modified noninvasive screening protocol for pulmonary hypertension in children with sickle cell disease-Who should be sent for invasive evaluation?

BACKGROUND: Invasive studies have shown that prevalence and severity of pulmonary hypertension (PH) in patients with sickle cell disease (SCD) tend to be overestimated if based exclusively on Doppler-derived tricuspid regurgitant velocity (TRV) as surrogate noninvasive marker with a cutoff ≥2.5 m/s. OBJECTIVES: We aimed to better define a subgroup of pediatric SCD patients who should be sent for invasive evaluation of pulmonary artery pressure (PAP) based on a modified echocardiographic PH screening protocol that implements evidence from Doppler-catheter comparative studies. STUDY DESIGN: Charts of 121 pediatric patients with stable SCD were reviewed regarding echocardiographically assessed risk for elevated PAP/PH and associated clinical characteristics. TRV cutoff was refined at ≥2.9 m/s to avoid overestimating the risk for PH. TRV was combined with additional echocardiographic parameters to avoid underestimating the PH risk. RESULTS: Ninety-one patients qualified for analysis. Based on our modified echocardiographic protocol, 5.5% of patients qualified for at least moderate risk for elevated PAP (compatible with PH) as opposed to 20.9% if based exclusively on TRV ≥2.5 m/s. These patients were older, homozygous for hemoglobin S (HbSS), and more anemic. No subject had an echocardiographic risk constellation suggesting more than mild PH. CONCLUSIONS: Our modified noninvasive screening protocol-if confirmed by invasive studies-may help to better identify a subgroup of pediatric SCD patients in whom evaluation by catheterization appears justified. Unlike estimates based on the conventional protocol, the size of the targeted subgroup compares favorably with catheterization-confirmed PH prevalence rates. Characteristics associated with an increased PH risk were also identified.

Maternal Polycystic Ovary Syndrome and Risk for Attention-Deficit/Hyperactivity Disorder in the Offspring.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, and boys are two to three times more likely to develop ADHD. Maternal polycystic ovary syndrome (PCOS), a common metabolic disorder associated with excess circulating androgens, has been associated with increased risk for autism spectrum disorder in the offspring. In this study, we aimed to investigate whether maternal PCOS increases the risk for ADHD in the offspring. METHODS: We conducted a matched case-control study using health and population data registers for all children born in Sweden from 1984 to 2008. Maternal PCOS was defined by ICD-coded register diagnosis. The outcome of ADHD was defined as an ICD-coded register diagnosis of ADHD and/or registered prescription of medications to treat ADHD. A total of 58,912 ADHD cases (68.8% male) were identified and matched to 499,998 unaffected controls by sex and birth month and year. RESULTS: Maternal PCOS increased the odds of offspring ADHD by 42% after adjustment for confounders (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.26-1.58). Exclusion of ADHD cases with comorbid autism spectrum disorder attenuated but did not explain the relationship (OR, 1.34; 95% CI, 1.18-1.52). The risk was somewhat elevated for ADHD with comorbid autism spectrum disorder (OR, 1.76; 95% CI, 1.37-2.26). The risk for ADHD was higher among obese mothers with PCOS (OR, 1.68; 95% CI, 1.31-2.17) and was highest among obese mothers with PCOS and other features of metabolic syndrome (OR, 2.59; 95% CI, 1.02-6.58). CONCLUSIONS: This study provides evidence that maternal PCOS may subtly influence the neurodevelopment of the offspring, resulting in increased risk for neurodevelopmental disorders such as ADHD.

Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine.

Accumulating data suggest a causative link between immune stimulation, disturbed metabolism of tryptophan, and pathogenesis of bipolar disorder and schizophrenia. The goal of this study was to examine the production of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes involved in their synthesis and metabolism in cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals. The assessment was performed under basal conditions or following treatment with interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, or their combinations, in cells exposed to exogenous kynurenine. In both groups of patients, the baseline production of KYNA and 3-HK was increased, as compared to control subjects. Case-treatment analyses revealed significant interactions between bipolar case status and IL-1ß, IL-6, IFN-γ + TNF-α, or IFN-γ + IL-1ß, as well as between schizophrenia case status and IL-1ß, IFN-γ + TNF-α, or IFN-γ + IL-1ß, in terms of higher 3-HK. Noteworthy, no case-treatment interactions in terms of KYNA production were found. Observed changes did not appear to correlate with the expression of genes encoding kynurenine aminotransferases (KATs), kynureninase (KYNU) or kynurenine-3-monooxygenase (KMO). The single nucleotide polymorphisms (SNPs), rs1053230 and rs2275163, in KMO influenced KYNA levels yet did not explain the case-treatment discrepancies. In conclusion, our present findings indicate the utility of skin-derived fibroblasts for kynurenines research and support the concept of kynurenine pathway alterations in bipolar disorder and schizophrenia. The increase in ratio between neurotoxic 3-HK and neuroinhibitory/neuroprotective KYNA following exposure to cytokines may account for altered neurogenesis and structural abnormalities characteristic for both diseases.

Early-life cadmium exposure and child development in 5-year-old girls and boys: a cohort study in rural Bangladesh.

BACKGROUND: Cadmium is a commonly occurring toxic food contaminant, but health consequences of early-life exposure are poorly understood. OBJECTIVES: We evaluated the associations between cadmium exposure and neurobehavioral development in preschool children. METHODS: In our population-based mother-child cohort study in rural Bangladesh, we assessed cadmium exposure in 1,305 women in early pregnancy and their children at 5 years of age by measuring concentrations in urine (U-Cd), using inductively coupled plasma mass spectrometry. Children's IQ at 5 years of age, including Verbal (VIQ), Performance (PIQ), and Full-Scale IQ (FSIQ), were measured by Wechsler Preschool and Primary Scale of Intelligence. Behavior was assessed by the Strengths and Difficulties Questionnaire (SDQ). RESULTS: In multiple linear regression models, adjusted for sex, home stimulation, socioeconomic status (SES), and maternal and child characteristics, a doubling of maternal U-Cd was inversely associated with VIQ (-0.84 points; 95% confidence interval: -1.3, -0.40), PIQ (-0.64 points; -1.1, -0.18), and FSIQ (-0.80 points; -1.2, -0.39). Concurrent child U-Cd showed somewhat weaker association with VIQ and FSIQ, but not PIQ. Stratification by sex and SES indicated slightly stronger associations with PIQ and FSIQ in girls than in boys and in higher-income compared with lower-income families. Concurrent U-Cd was inversely associated with SDQ-prosocial behavior and positively associated with SDQ-difficult behavior, but associations were close to the null after adjustment. Quantile regression analysis showed similar associations across the whole range of each developmental outcome. CONCLUSION: Early-life low-level cadmium exposure was associated with lower child intelligence scores in our study cohort. Further research in this area is warranted.

Iron deficiency reduces serum and in vitro secretion of interleukin-4 in mice independent of altered spleen cell proliferation.

Iron deficiency, a worldwide public health problem in children and adult women, impairs innate and cell-mediated immunity including interferon-γ secretion. Its effects on interleukin (IL)-4 have not been well investigated. Interleukin-4, a cytokine primarily secreted by TH2 lymphocytes, regulates B-cell proliferation and the switching of immunoglobulin (Ig)M to IgE subtypes; the latter is involved in the defense against helminth infection. Considering the fact that interferon-γ is a potent inhibitor of IL-4, we hypothesize that iron deficiency would increase the secretion of IL-4 and IgE. We measured IL-4 in serum and supernatant of concanavalin A and anti-CD3 antibody-treated spleen cells from iron-deficient, control, pair-fed DBA and C57BL/6 mice (20-24/group) and iron-replete mice for 3, 7, and 14 days (8-13/group). Feeding the low-iron diet (5 ppm vs 50 ppm for the control diet) for 2 months significantly reduced the mean levels of hemoglobin, hematocrit, liver iron stores, thymus weight, and induced splenomegaly in both strains of mice (P < .001). Iron deficiency, and not pair-feeding, reduced plasma IL-4 levels (P < .05), although it did not significantly affect IgE levels. Iron deficiency, especially when associated with thymus atrophy, reduced in vitro IL-4 secretion by activated spleen cells, cell proliferation, and percentage of CD4⁺IL-4⁺ cells (P < .05). Impaired cell proliferation did not fully explain reduced in vitro IL-4 secretion because iron-deficient mice with a normal thymus weight had a normal (3)H-thymidine uptake but decreased supernatant IL-4. It was likely due to low percentage of CD4⁺IL-4⁺. Iron repletion improved IL-4 measurements. Data suggest that iron deficiency has generalized negative effects on T-cell function. Unaltered plasma IgE may be due to other cytokines (ie, IL-13) that also modulate its secretion.

Maternal cadmium exposure during pregnancy and size at birth: a prospective cohort study.

BACKGROUND: Cadmium (Cd) is an embryotoxic and teratogenic metal in a variety of animal species, but data from humans are limited. OBJECTIVES: The aim of the present study was to assess the effects of maternal Cd exposure in pregnancy on size at birth. METHODS: This prospective cohort study was nested in a population-based nutritional supplementation trial in pregnancy conducted in rural Bangladesh. We selected women recruited from February 2002 through January 2003 who had a singleton birth with measurements of size at birth and had donated a urine sample in early pregnancy for Cd analyses (n = 1,616). Urinary Cd was measured with inductively coupled plasma mass spectrometry and adjusted for specific gravity. RESULTS: Multiple linear regression analyses adjusted for sex and other potential confounders showed that maternal urinary Cd (median, 0.63 µg/L) was significantly negatively associated with birth weight [unstandardized regression coefficient B = -31.0; 95% confidence interval (CI): -59, -2.8] and head circumference (B = -0.15; 95% CI: -0.27, -0.026). However, associations appeared to be limited to girls, with little evidence of effects in boys. A 1-µg/L increase in Cd in maternal urine was associated with a 0.26-cm (95% CI: -0.43, -0.088 cm) and 0.24-cm (95% CI: -0.44, -0.030 cm) decrease in girls' head and chest circumferences, respectively, and a 45-g (95% CI: -82.5, 7.3 g) decrease in birth weight. Quantile regression analyses indicated that associations with maternal Cd were similar for girls of smaller (25th percentile) and larger (50th and 75th percentiles) sizes at birth. CONCLUSION: We found evidence of a sex difference in the association between maternal Cd exposure and birth size, which was apparent only in girls. Results add support for the need to reduce Cd pollution to improve public health.

Brief report: maternal smoking during pregnancy and autism spectrum disorders.

Prenatal exposure to tobacco smoke is suggested as a potential risk factor for autism spectrum disorders (ASD). Previous epidemiological studies of this topic have yielded mixed findings. We performed a case-control study of 3,958 ASD cases and 38,983 controls nested in a large register-based cohort in Sweden. ASD case status was measured using a multisource case ascertainment system. In adjusted results, we found that maternal smoking during pregnancy is not associated with increased risk of ASD regardless of presence or absence of comorbid intellectual disability. Apparent associations were attributable to confounding by sociodemographic characteristics of parents such as education, income, and occupation.

Long-term safety and efficacy of deferasirox (Exjade) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease.

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 µg/l (95% confidence intervals, -1411, -280 µg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.

Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood.

BACKGROUND: Arsenic (As) exposure during pregnancy induces oxidative stress and increases the risk of fetal loss and low birth weight. OBJECTIVES: In this study we aimed to elucidate the effects of As exposure on immune markers in the placenta and cord blood, and the involvement of oxidative stress. METHODS: Pregnant women were enrolled around gestational week (GW) 8 in our longitudinal, population-based, mother-child cohort in Matlab, an area in rural Bangladesh with large variations in As concentrations in well water. Women (n = 130) delivering at local clinics were included in the present study. We collected maternal urine twice during pregnancy (GW8 and GW30) for measurements of As, and placenta and cord blood at delivery for assessment of immune and inflammatory markers. Placental markers were measured by immunohistochemistry, and cord blood cytokines by multiplex cytokine assay. RESULTS: In multivariable adjusted models, maternal urinary As (U-As) exposure both at GW8 and at GW30 was significantly positively associated with placental markers of 8-oxoguanine (8-oxoG) and interleukin-1ß (IL-1ß); U-As at GW8, with tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); and U-As at GW30, with leptin; U-As at GW8 was inversely associated with CD3+ T cells in the placenta. Cord blood cytokines (IL-1ß, IL-8, IFNγ, TNFα) showed a U-shaped association with U-As at GW30. Placental 8-oxoG was significantly positively associated with placental proinflammatory cytokines. Multivariable adjusted analyses suggested that enhanced placental cytokine expression (TNFα and IFNγ) was primarily influenced by oxidative stress, whereas leptin expression appeared to be mostly mediated by As, and IL-1ß appeared to be influenced by both oxidative stress and As. CONCLUSION: As exposure during pregnancy appeared to enhance placental inflammatory responses (in part by increasing oxidative stress), reduce placental T cells, and alter cord blood cytokines. These findings suggest that effects of As on immune function may contribute to impaired fetal and infant health.

Iron deficiency, but not underfeeding reduces the secretion of interferon-gamma by mitogen-activated murine spleen cells.

Interferon-gamma (IFN-γ), a cytokine primarily secreted by T and natural killer cells regulates cell-mediated and innate immunity. Iron deficiency, a public health problem in children impairs immune function. To determine whether reduced IFN-γ contributes to impaired immunity, we measured IFN-γ in supernatants of activated (2.5 µg/ml concanavalin A, 50 ng/ml anti-CD3 antibody) spleen cells from control (C), iron-deficient (ID), pair-fed (PF), and iron-replete mice for 3 (R3) and 14 days (R14) (11-12/group). Except for iron content, the low iron (5 ppm) and control (50 ppm) diets had identical composition. Mean indices of iron status after 51 days of feeding were as follows: C=PF≈R14>R3>ID (p<0.01). Iron deficiency, but not pairfeeding reduced IFN-γ concentration in mitogen-treated cells by 30-43% (p<0.05); iron repletion improved it. Reduced IFN-γ was not simply due to differences in IL-12 (IFN-γ inducer), percentage of CD3+ T cells, or impaired cell proliferation because these indices were not always decreased. It was likely due to a defect in T cell activation that leads to IFN-γ gene expression. IFN-γ positively correlated with indicators of iron status, body, and thymus weights (r=0.238-0.472; p<0.05). Reduced IFN-γ secretion during iron deficiency may affect response to infections.

Effect of L-arginine supplementation on immune responsiveness in patients with sickle cell disease.

BACKGROUND: L-arginine (L-Arg) is deficient in sickle cell disease (SSD) during vasoocclusion. We investigated possible causal relationship between L-Arg deficiency and immune dysfunction in SSD in steady-state. PROCEDURE: Fifteen patients with SSD in steady-state and 13 controls were studied. Plasma L-Arg levels were measured using liquid chromatography. T cell subsets and CD3zeta (CD3zeta) chain expression were analyzed using flow cytometry. Lymphocyte proliferative response to phytohemagglutinin (PHA) and production of IL-6 and interferon-gamma (IFN-gamma) were evaluated with and without L-Arg. RESULTS: SSD patients had significantly lower L-Arg levels than controls. CD3 and CD19 cell populations were comparable for both groups, but SSD patients had above normal numbers of natural killer cells (P = 0.06). Patients and controls exhibited significantly increased lymphocyte blastogenesis to PHA after introduction of L-Arg to cultures; response of patients was significantly greater than values for control individuals. Proliferative response to candida in SSD patients was significantly lower than in controls; L-Arg supplementation did not increase this response. L-Arg had no effect on blastogenic response to PPD and candida albicans. No effect was likewise seen in production of IL-6 and IFN-gamma after addition of L-Arg. CD3zeta chain expression increased after addition of L-Arg in both groups; differences were insignificant. CONCLUSION: L-Arg levels in steady-state SSD are significantly lower than in controls. L-Arg supplementation enhanced lymphocyte blastogenesis to PHA for both controls and patients, but not in response to antigen. There were no significant differences in CD3zeta chain expression although upregulation of expression occurred after L-Arg supplementation for both groups.

Mercury exposure, serum antinuclear/antinucleolar antibodies, and serum cytokine levels in mining populations in Amazonian Brazil: a cross-sectional study.

Mercury is an immunotoxic substance that has been shown to induce autoimmune disease in rodent models, characterized by lymphoproliferation, overproduction of immunoglobulin (IgG and IgE), and high circulating levels of auto-antibodies directed at antigens located in the nucleus (antinuclear auto-antibodies, or ANA) or the nucleolus (antinucleolar auto-antibodies, or ANoA). We have reported elevated levels of ANA and ANoA in human populations exposed to mercury in artisanal gold mining, though other confounding variables that may also modulate ANA/ANoA levels were not well controlled. The goal of this study is to specifically test whether occupational and environmental conditions (other than mercury exposure) that are associated with artisanal gold mining affect the prevalence of markers of autoimmune dysfunction. We measured ANA, ANoA, and cytokine concentrations in serum and compared results from mercury-exposed artisanal gold miners to those from diamond and emerald miners working under similar conditions and with similar socio-economic status and risks of infectious disease. Mercury-exposed gold miners had higher prevalence of detectable ANA and ANoA and higher titers of ANA and ANoA as compared to diamond and emerald miners with no occupational mercury exposure. Also, mercury-exposed gold miners with detectable ANA or ANoA in serum had significantly higher concentrations of pro-inflammatory cytokines IL-1beta, TNF-alpha, and IFN-gamma in serum as compared to the diamond and emerald miners. This study provides further evidence that mercury exposure may lead to autoimmune dysfunction and systemic inflammation in affected populations.