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For the past decades, international courts and tribunals have eluded the question of whether a State’s entitlement to a continental shelf beyond 200 nautical miles (nm) may extend within 200 nm of another State. The opacity around this question steered the International Court of Justice to surprisingly divide its oral proceedings in the pending dispute between Nicaragua and Colombia, so that it could address this legal predicament first. In similar circumstances, the International Tribunal for the Law of the Sea asked Mauritius and The Maldives to deal with the same question. While this is not the first time an international court or tribunal is asked to delimit a continental shelf beyond 200 nm, it will be the first where the ‘legal’ and the ‘geophysical’ entitlements enshrined in Article 76(1) of UNCLOS face each other. This article examines the current state of international law and proposes that the overlap between both entitlements is legally permissible, but the ‘legal’ entitlement enjoys further normative strength and will guide the equitable delimitation of the continental shelf.

This article examines how the detention or deportation of a parent shapes the roles and responsibilities of young adults within the household and the consequences that these changes have on their educational experiences. Drawing from thirty-two in-depth interviews with young adults living in the United States whose parent was detained, author Carolina Valdivia finds that children’s responsibilities within the family abruptly change as soon as a parent is apprehended, with conditions worsening as the parent undergoes deportation proceedings. More specifically, young adults take on additional and a wider range of responsibilities to help their families cope emotionally and financially, including working additional jobs and spending more time taking care of younger siblings. The article also demonstrates how young adults’ gender, birth order, and level of education at the time of a parent’s immigration arrest shape their participation at home and notes how increased responsibilities affect their educational trajectories.

Introduction: Concerns about children’s intake of fluoride toothpaste are limitedto infancy due to the risk of fluorosis in the permanent anterior teeth, but theeducational process to ensure safety for the entire dentition has been neglected.Objective: To report a case of dental fluorosis in canine, premolar and 2nd molarteeth caused by voluntary ingestion of fluoride toothpaste. Case report: A 12-year-old patient, 65 kg, search dental care due to dissatisfaction with the color ofthe posterior teeth. It was diagnosticated that the superior and inferior canine,premolar and second molar teeth had fluorotic opacities, and the other teeth aresound. Among the possible causes, the main one was the way the child startedbrushing their teeth after 5 years of age. It was reported that she voluntarilybrushed her teeth 6x/day without spitting. Analyzes of the fluoride concentrationin the water consumed by the patient and in the toothpastes used were performed.A urinary fluoride excretion test by the patient, requesting her to brush her teethby spitting out or swallowing all the toothpaste in use, was made. Results: Fluorideconcentration in the water was 0.74 mg F/L and 1,357 and 1,426 mg F/kg in thetoothpastes pastes used. In urine test, 0.90 and 1.35 mg F were found, respectively,spitting or swallowing the toothpaste after brushing. It was estimated that from 5years of age, the child was submitted a dose of 0.17 mg F/day/kg of body weight,which is 2.4 times the upper limit for an acceptable fluorosis. Conclusion: Thereported case suggests that it is a consequence of the failure of the health educationprocess in early childhood regarding the rational use of fluoride toothpaste. Introdução: Preocupações com a ingestão de pasta fluoretada por crianças se limita à primeira infância devido ao risco de fluorose nos dentes permanentes anteriores, mas o processo educativo para garantir uma segurança para toda a dentição tem sido negligenciado. Objetivo: Relatar um caso de fluorose dentaria em dentes caninos, pré-molares e 2o molares por ingestão voluntária de pasta fluoretada Relato do caso: Paciente de 12 anos, 65 kg, procurou atendimento odontológico devido a insatisfação com a coloração dos dentes posteriores. Constatou-se que os dentes caninos, pré-molares e segundo molares, superiores e inferiores apresentavam opacidades tipo fluoróticas, estando os demais normais. Entre as possíveis causas, a principal recaiu sobre o modo que a criança passou a escovar os dentes após os 5 anos de idade. Foi relatado que ela voluntariamente escovava seus dentes 6x/dia sem cuspir. Foram feitas análises da concentração de fluoreto da água consumida pela paciente e nas pastas usadas. Também foi feito teste de excreção de fluoreto urinário pela paciente, solicitando para ela escovar os dentes cuspindo ou engolindo toda a pasta em uso. Resultados: Na água foi encontrado 0,74 mg F/L e nas pastas usadas 1.357 e 1.426 mg F solúvel/ kg. Na urina foi encontrado 0,90 e 1,35 mg F, respectivamente, cuspindo ou engolindo a pasta após as escovações. Foi estimado que a partir dos 5 anos de idade, a criança se submeteu à dose de 0,17 mg F/dia/kg de peso corpóreo, a qual é 2,4 vezes maior que o limite superior de risco de fluorose. Conclusão: O caso relatado sugere ser uma consequência de falha do processo de educação em saúde na 1a infância quanto ao uso racional de dentifrício fluoretado.

Resumo Os dentifrícios fluoretados comercializados para crianças devem conter concentração mínima de 1000 ppm de fluoreto (F), que deve ser quimicamente solúvel para ter efeito anticárie. Portanto, determinamos as concentrações de fluoreto total (FT) e fluoreto solúvel total (FST) em dentifrícios comercializados para crianças no Brasil e no México e analisamos as regulamentações vigentes em ambos os países. Vinte e quatro marcas foram encontradas e adquiridas no Brasil (19 formuladas com NaF/SiO2, três com Na2FPO3/CaCO3 e duas com Na2FPO3/SiO2) e seis no México (todas com NaF/SiO2). As concentrações de FT e FST foram determinadas após a compra (amostras frescas), e a estabilidade do fluoreto nas formulações de Na2FPO3/CaCO3 foi verificada após 18 meses. As análises foram realizadas com eletrodo íon-específico e os resultados expressos em ppm F (mg F/kg). As concentrações de FT encontradas variaram de 476,0 a 1.385,3 ppm F e foram próximas às declaradas pelos fabricantes (500 a 1.450 ppm F). As concentrações de FT encontradas não ultrapassaram 1.500 ppm F, de acordo com as regulamentações vigentes de ambos os países. No entanto, dentifrícios com concentrações de FST inferiores a 1.000 ppm F foram encontrados tanto em dentifrício com baixa concentração (500 ppm F) formulado com NaF/SiO2 como em dentifrícios com Na2FPO3/CaCO3 frescos e envelhecidos, originalmente fabricados com 1.000-1.100 ppm de FT. Em conclusão, embora a maioria dos dentifrícios analisados apresentasse concentração de FST superior a 1.000 ppm F, as regulamentações vigentes em ambos os países permitem que produtos que não estejam de acordo com a melhor evidência disponível estejam presentes no mercado. Abstract Fluoride toothpastes market to children should contain a minimum concentration of 1000 ppm of fluoride (F), which must be chemically soluble to provide anti-caries effect. Therefore, we determined the concentrations of total fluoride (TF) and total soluble fluoride (TSF) in toothpastes marketed to children in Brazil and Mexico and analyzed the current regulations in force in both countries. Twenty-four brands were found and purchased in Brazil (19 formulated with NaF/SiO2, three with Na2FPO3/CaCO3 and two with Na2FPO3/SiO2) and six in Mexico (all with NaF/SiO2). TF and TSF concentrations were determined after the purchase (fresh samples) but fluoride stability in Na2FPO3/CaCO3-formulations was checked after 18 months. The analyses were performed with an ion-specific electrode and the results expressed in ppm F (mg F/kg). The TF concentrations found ranged from 476.0 to 1385.3 ppm F and they were close the declared by the manufactures (500 to 1450 ppm F). The TF concentrations found were not greater than 1500 ppm F, in accordance with the current regulations of both countries. However, toothpastes presenting TSF concentrations lower than 1000 ppm F were found either in low fluoride toothpaste (500 ppm F) formulated with NaF/SiO2 as in fresh and aged Na2FPO3/CaCO3-toothpastes, originally fabricated with 1000-1100 ppm of TF. In conclusion, although most toothpastes analyzed showed TSF concentration higher than 1000 ppm F, the regulations in force in both countries allow that products not in agreement with the best available evidence are available in the market.

The day-to-day behaviors of undocumented immigrants are significantly affected when local law enforcement officials do the work of federal immigration enforcement. One such behavior, which has been widely discussed in debates over so-called sanctuary policies, is that undocumented immigrants are less likely to report crimes to the police when local law enforcement officials work with U.S. Immigration and Customs Enforcement (ICE) on federal immigration enforcement. However, the mechanism that explains this relationship of decreased trust in law enforcement has not yet been systematically tested. Do undocumented immigrants become less trusting of police officers and sheriffs when local law enforcement officials work with ICE on federal immigration enforcement? To answer this, we embedded an experiment that varied the interior immigration enforcement context in a survey (n = 512) drawn from a probability-based sample of undocumented immigrants. When local law enforcement officials work with ICE on federal immigration enforcement, respondents are statistically significantly less likely to say that they trust that police officers and sheriffs will keep them, their families, and their communities safe; will protect the confidentiality of witnesses to crimes even if they are undocumented; will protect the rights of all people equally, including undocumented immigrants; and will protect undocumented immigrants from abuse or discrimination.

The ability of mouth rinses, available in the international market, to form reaction products on demineralized enamel (bioavailability test) was evaluated in vitro. Nine mouth rinses purchased in Chile were evaluated; eight formulated with NaF (one containing 100 µg F/mL and seven containing 226) and one with Na2FPO3 (226 µg F/mL as ion F). Demineralized enamel slabs (n=15 per mouth rinse) were sectioned; one half was subjected to the assigned mouth rinse treatment for 10 min and the other half was used to obtain baseline data. Loosely bound and firmly bound fluoride formed on enamel were determined with an ion-specific electrode and the values were expressed in µg F/cm2. The concentration of fluoride and the pH of the mouth rinses were previously determined. Concentrations of loosely bound and firmly bound fluoride formed on enamel were independently analyzed by ANOVA and Tukey’s test (α=5%). The loosely bound and firmly bound fluoride concentrations (µg F/cm2) formed ranged from 3.2 to 36.2 and 0.4 to 1.7, respectively. Loosely bound fluoride formed on enamel was significantly more effective in discriminating the effect of different commercial mouth rinses than firmly bound fluoride. Mouth rinses with 226 ppm F as NaF and low pH presented significantly greater bioavailability of fluoride on enamel than those with higher pH or lower NaF concentration. The mouth rinse with Na2FPO3 showed low reactivity. Although further studies are necessary, the findings showed that commercial fluoride-containing mouth rinses have important variations in enamel fluoride bioavailability, which may result in differences on anticaries efficacy. Resumo Os enxaguatórios bucais comerciais fluoretados diferem na concentração e tipo de sal de fluoreto, no pH e têm alguns ingredientes que podem interferir na reatividade do fluoreto com o esmalte desmineralizado. A capacidade de enxaguatórios bucais comerciais de formar produtos de reação em esmalte desmineralizado (teste de biodisponibilidade) foi avaliada in vitro. Nove enxaguatórios bucais adquiridos no Chile foram avaliados, oito formulados com NaF (um contendo 100 µg F/mL e sete contendo 226) e um com Na2FPO3 (226 µg F/mL como íon F). Os blocos de esmalte desmineralizados (n=15 por grupo) foram seccionados, uma metade foi submetida ao tratamento com o enxaguatório designado por 10 min e a outra metade foi usada para dados baseline. Fluoreto fracamente e firmemente ligados formados no esmalte foram determinados com um eletrodo íon-específico e os valores foram expressos em µg F /cm2. A concentração de fluoreto e o pH dos enxaguatórios foi previamente determinada. As concentrações de fluoreto tipo fluoreto fracamente ligado e fortemente ligado formadas no esmalte foram analisadas independentemente por ANOVA e teste de Tukey (α=5%). As concentrações de fluoreto fracamente ligado e fortemente ligado formados variaram de 3,2 a 36,2 e 0,4 a 1,7, respectivamente. O fluoreto fracamente ligado formado no esmalte foi significativamente mais eficaz para discriminar o efeito dos diferentes enxaguatórios bucais comerciais do que o fluoreto firmemente ligado. Enxaguatórios bucais com 226 ppm F na forma de NaF e baixo pH apresentaram significativamente maior biodisponibilidade de fluoreto no esmalte do que aqueles com maior pH ou menor concentração de NaF. O enxaguatório com Na2FPO3 apresentou reatividade muito baixa. Embora mais estudos sejam necessários, os resultados mostraram que os enxaguatórios bucais comerciais contendo fluoreto apresentam variações importantes na biodisponibilidade do fluoreto, o que poderia resultar em diferenças na eficácia anticárie.

The ability of mouthrinses, available in the international market, to form reaction products on demineralized enamel (bioavailability test) was evaluated in vitro. Nine mouthrinses purchased in Chile were evaluated; eight formulated with NaF (one containing 100 µg F/mL and seven containing 226) and one with Na2FPO3 (226 µg F/mL as ion FPO3 ). Demineralized enamel slabs (n=15 per mouthrinse) were sectioned; one half was subjected to the assigned mouthrinse treatment for 10 min and the other half was used to obtain baseline data. Loosely bound and firmly bound fluoride formed on enamel were determined with an ion-specific electrode and the values were expressed in µg F/cm2. The concentration of fluoride and the pH of the mouthrinses were previously determined. Concentrations of loosely bound and firmly bound fluoride formed on enamel were independently analyzed by ANOVA and Tukey’s test (α=5%). The loosely bound and firmly bound fluoride concentrations formed ranged from 3.2 to 36.2 and 0.4 to 1.7, respectively. Loosely bound fluoride formed on enamel was significantly more effective in discriminating the effect of different commercial mouthrinses than firmly bound fluoride. Mouthrinses with 226 ppm F as NaF and low pH presented significantly greater bioavailability of fluoride on enamel than those with higher pH or lower NaF concentration. The mouthrinse with Na2FPO3 showed low reactivity. Although further studies are necessary, the findings showed that commercial fluoride-containing mouthrinses have important variations in enamel fluoride bioavailability, which may result in differences on anticaries efficacy.

For fluoride to be effective in controlling caries, it should be bioavailable in commercial products, so that it can be released into the mouth in the products it contains. We chemically determined the available fluoride and pH in nine mouth rinses marketed in Chile, and eleven, in Brazil, and then discussed the legislation in force in both countries, regarding the anticaries potential of these oral hygiene products. The fluoride was analyzed with an ion-selective electrode (F-ISE), using the direct technique. The determinations were made in duplicate, and the results were expressed in ppm F (μg F/mL). The total fluoride concentration found in all the mouth rinses evaluated ranged from 94.7 to 233.5 ppm F, and closely matched what was declared by the manufacturers (100.0 to 226.2 ppm F). However, some mouth rinses showed lower fluoride concentrations (90 and 180 ppm F) in both countries. A Na2FPO3-formulated mouth rinse was found only in Chile, with 216.8 ppm F as the FPO32- ion, and 4.9 ppm F as the F-. The findings show that fluoride was potentially bioavailable in all the mouth rinses evaluated. Regarding the national legislations, although the mouthwashes sold in Brazil comply with the Brazilian legislation, discrepancies were found for Chile. However, neither country had a legislation matching the best available evidence on fluoride mouthwash efficacy for caries control. Thus, some products with low fluoride concentrations (below 226 ppm F), or manufactured with a fluoride salt other than NaF (Na2FPO3) are being sold in the Brazilian and Chilean markets.

This article examines the impact of policies and programs that have expanded immigration enforcement from the federal to the local level. Drawing from in‐depth interviews with over sixty individuals who are members of undocumented or mixed‐status families, I discuss how these initiatives have extended the geography of deportability from traditional sites that focus explicitly on immigration enforcement (e.g., the US–Mexico border) to more nontraditional sites in the public sphere (e.g., driving under the influence checkpoints or grocery stores). I demonstrate how this intensification of enforcement strains undocumented immigrants’ resources as well as their participation in school, work, and their communities.

BACKGROUND High sodium intake has been associated with various noncommunicable disease like hypertension, cardiovascular disease, or stroke. To estimate accurately sodium intake is challenging in clinical practice. We investigate the usefulness and limitations of assessing sodium intake simultaneously by dietary assessment and urinary samples in both children and adults. METHODS We used a cross-sectional study design inviting 298 Chilean subjects (74 children and 222 adults) aged between 9 and 66 years of both genders. Sodium intake by dietary assessment was obtained from Chilean food composition data, based on FAO tables. Sodium and creatinine excretion were measured in 24-hour urine samples, in all participants. RESULTS Adequate urinary collection was obtained in 81% of children (59/74) and 61% of adults (135/222). The mean sodium intake by dietary assessment was similar to the sodium excretion in 24 hours (3,121±1,153mg/d vs. 3,114±1,353mg/24h, P = nonsignificant) in children but was significantly lower (3,208±1,284mg/d vs. 4,160±1,651mg/24h, P < 0.001) in adults. In both children and adults, sodium intake correlated with urinary sodium excretion (r = 0.456, P < 0.003 and r = 0.390, P < 0.001, respectively). Secondary analyses also suggested that the dietary assessment was more inaccurate in overweight adult subjects. CONCLUSIONS Our results showed that average sodium intake was higher than recommended in both children and adults (WHO ≤2,000mg/d). The sodium intake estimated by dietary assessment correlated with urinary excretion in all subjects, but in obese adults was more inaccurate than in children. Future studies to validate the appropriate test to assess sodium intake by age and nutritional status are warranted.

Context Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by severe 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio. Objective To evaluate nonclassic AME (NC-AME) due to partial 11β-HSD2 insufficiency and its association with hypertension, mineralocorticoid receptor (MR) activation, and inflammatory parameters. Design Cross-sectional study. Setting Primary care cohort. Participants We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. We measured clinical, biochemical, renal, vascular, and inflammatory variables. Sequencing of HSD11B2 gene was performed in all subjects. Main Outcome Measure NC-AME. Results Serum F/E ratio was positively associated with systolic blood pressure (BP), microalbuminuria, and high-sensitivity C-reactive protein (hs-CRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, body mass index, and sex: lower cortisone with higher potassium excretion (partial r = -0.29, P = 0.002) and with lower plasma renin activity (PRA) (partial r = 0.29, P = 0.001). Consistently, we identified 9 in 127 subjects (7.1%) with high F/E ratios (first quartile) and low cortisone (last quartile), suggestive of NC-AME. These subjects had higher systolic BP, 141.4 ± 25.7 mm Hg vs 127.3 ± 18.1 mm Hg, P = 0.03; lower PRA, 0.36 ± 0.19 ng/L*s vs 0.64 ± 0.47 ng/L*s, P < 0.0001; and greater potassium excretion, microalbuminuria, hs-CRP, and plasminogen activator inhibitor. We only found in 2 out of 9 subjects with NC-AME heterozygous mutations in the HSD11B2 gene. Conclusions These findings suggest a spectrum of partial 11β-HSD2 insufficiency in a primary care cohort without the classic phenotype and genotype of AME. NC-AME may represent a phenotype of MR activation and cardiovascular risk, suggesting that these subjects could be treated with MR antagonists.

BACKGROUND The impairment of 11β-hydroxysteroid dehydrogenase type 2 enzyme (11βHSD2) results in an inefficient conversion of cortisol to cortisone, which triggers hypertension. Cytosine-adenine repeat (CA repeat) microsatellite has been associated with low HSD11B2 gene expression. AIM To determine whether the CA-repeat length in intron 1 affect the serum cortisol to cortisone (F/E) ratio and/or blood pressure (BP) levels in pediatric subjects. SUBJECTS AND METHODS Eighty-one hypertensive (HT) and 117 normotensive (NT) subjects participated in this study. We measured BP levels, as well as the F and E and F/E ratio in morning sera and 12-hour urine samples. The length of CA repeats was determined through fragment analysis. We compared the allele distribution between the HT and NT groups, and the patients were dichotomized into groups with short alleles (S) (

BACKGROUND Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11βHSD2 deficiency in those heterozygous subjects. METHODS We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS The normal values (median [interquartile range]) in children for serum F/E and cortisone (µg/dl) were 2.56 [2.21–3.69] and 2.54 [2.35–2.88], and in adults were 4.42 [3.70–4.90] and 2.23 [1.92–2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 µg/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 µg/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION Serum F/E ratio and cortisone allow to identify partial 11βHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension.

In the context of an unequal global economy, families increasingly have to make the difficult decision to migrate as a strategy for survival, which leads to family separation. In 2014, family separ...

To identify novel biomarkers associated with pediatric primary hypertension.We recruited 350 participants (4-16 years). Anthropometric parameters and aldosterone, plasma renin activity, cortisol, cortisone, Homeostasis Model Assessment Insulin Resistance (HOMA-IR), high-sensitivity C-reactive protein, adiponectin, IL-6, plasminogen activator inhibitor type 1 levels and matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9 and MMP-2) activities were measured. Genomic DNA was isolated. Patients with altered glucose metabolism, severe obesity [BMI-SD score (BMI-SDS) 2.5], renovascular disease, primary aldosteronism and apparent mineralocorticoid excess syndrome were excluded.In selected participants (n = 320), SBP was positively correlated with BMI-SDS (r = 0.382, P 0.001), HOMA-IR (r = 0.211, P 0.001), MMP-9 activity (r = 0.215, P 0.001) and the cortisol/cortisone ratio (r = 0.231, P 0.001). DBP showed similar correlations with these variables. No correlation was observed with aldosterone or plasma renin activity. Participants were categorized as hypertensive (n = 59) or nonhypertensive (n = 261). In the univariate analysis, hypertensive patients had higher BMI-SDS (P 0.001), HOMA-IR (P 0.001), high-sensitivity C-reactive protein (P 0.001), MMP-9 activity (P 0.001), plasminogen activator inhibitor type 1 (P 0.001) and cortisol/cortisone ratio (P 0.001) than nonhypertensive patients. Multiple regression analysis showed that the variables that remained associated with hypertension were higher BMI-SDS [odds ratio (OR) = 3.74; 95% confidence interval (CI) = 1.84-7.58], a higher cortisol/cortisone ratio (OR = 3.92; 95% CI = 1.98-7.71) and increased MMP-9 activity (OR = 4.23; 95% CI = 2.15-8.32).We report that MMP-9 activity and the cortisol/cortisone ratio were higher in pediatric primary hypertensive patients, and these associations were independent of the effect of obesity. The potential role of these novel biomarkers in predicting hypertension risk and blood pressure regulation warrants further investigation.

In Everyday Illegal, Joanna Dreby explores how illegality affects the lives of immigrant families within an increasingly restrictive immigration context. Her contribution to the literature on undoc...

background Rac1 upregulation has been implicated in salt-sensitive hypertension as a modulator of mineralocorticoid receptor (MR) activity. Rac1 could affect the expression of oxidative stress markers, such as hemoxigenase-1 (HO1) or nuclear factor-B (NF-κB), and the expression of neutrophil gelatinaseassociated lipocalin (NGAL), a cytokine upregulated upon MR activation. aim We evaluated RAC1 expression in relation of high salt intake and association with MR, NGAL, HO-1, and NF-κB expression, mineralo- and glucocorticoids levels, and inflammatory parameters. subjects and methods We studied 147 adult subjects. A food survey identified the dietary sodium (Na) intake. RAC1 expression was considered high or low according to the value found in normotensive subjects with low salt intake. We determined the gene expression of RAC1, MR, NGAL, HO-1, NF-κB, and 18S, isolated from peripheral leukocytes. We measured aldosterone, cortisol, sodium, potassium excretion, metalloproteinase (MMP9 y MMP2), and C-reactive protein. results We identified 126 subjects with high Na-intake, 18 subjects had high, and 108 low-RAC1 expression. The subjects with high-RAC1 expression showed a significant increase in MR (P = 0.0002), NGAL (P < 0.0001) HO-1 (P = 0.0004), and NF-κB (P < 0.0001) gene expression. We demonstrated an association between RAC1 expression and MR (Rsp 0.64; P

Historically, immigration policy has defined those who belonged and those who have been excluded from US society. This carried significant consequences to the everyday existence of those affected b...

The GTPase Rac1 has been implicated in hypertension as a modulator of mineralocorticoid receptor activity. Our aim is to investigate the frequency of polymorphisms rs10951982 (intron 1, GA) and rs836478 (intron 3, TC) in the RAC1 gene and perform association studies with clinical and biochemical parameters in a Chilean pediatric cohort.Two hundred two normotensive (NT) subjects (aged 4-16 years) were divided into 2 groups: NT subjects with hypertensive parents (NH; n = 103) and NT subjects with NT parents (NN; n = 99). We measured markers of inflammation (high-sensitivity C-reactive protein, interleukin 6 (IL-6), interleukin 8, and tumor necrosis factor α), endothelial damage (Plasminogen activator inhibitor-1 metalloproteinase-9, and metalloproteinase-2), and oxidative stress (malondialdehyde). Data were expressed as median and interquartile range (IQR).We found differences in polymorphism rs836478 (intron 3, CT) in both genotypic (χ(2) = 15.2, 2 df; P = 0.0005) and allelic (X(2)=5.5, 1 df; P = 0.01) frequencies in NH vs. NN subjects. NH subjects with a TT genotype showed increase MMP9 expression (median = 2.3, IQR - 1.6-3.2; vs. median = 1.6, IQR = 1.6-2.3 AU; P = 0.01) and lower IL-6 expression (median = 8.8, IQR = 7.0-11.8; vs. median = 12.1, IQR = 8.2-14.7 pg/ml; P = 0.02) compared with subjects with TC/CC genotype. No difference in the allelic frequency distribution was seen in the polymorphism rs10951982 (NH vs. NN: χ(2)=0.2, 1 df; P = 0.6). For this SNP, NN subjects with GA/AA genotype showed decreased diastolic BP indexes compared with subjects with native GG genotype (median = 1.08, IQR = 1.0-1.2; vs. median = 0.99, IQR = 0.94-1.1; P = 0.02).We report the frequency of polymorphisms rs836478 and rs10951982 of the RAC1 gene in a Spanish-Amerindian cohort. The polymorphism rs836478 was associated with an increased expression in markers of inflammation and endothelial damage (MMP9 and IL-6) in pediatric subjects with a hypertensive genetic background.

11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to cortisol in a NADPH dependent manner. Overexpression of 11β-HSD1 in key metabolic tissues is related to the development of type 2 diabetes, obesity, hypertension and metabolic syndrome. Using crystal structures of human 11β-HSD1 in complex with inhibitors as source of structural information, a combined ligand and structure-based virtual screening approach was implemented to identify novel 11β-HSD1 inhibitors. A selected group of compounds was identified in silico and further evaluated in cell-based assays for cytotoxicity and 11β-HSD1 mediated cortisol production inhibitory capacity. The expression of 11β-HSD1 and 11β-HSD2 in human LS14 adipocytes was assessed during differentiation. Biological evaluation of 39 compounds in adipocytes and steroids quantification by HPLC-MS/MS identify 4 compounds that exhibit 11β-HSD1 mediated cortisol production inhibitory activity with potencies in the micromolar range. Two compounds showed to be selective for the 11β-HSD1 reductase activity and over 11β-HSD2 isoform, and thus represent novel leads for the development of more active derivatives with higher efficacies targeting intracellular cortisol levels in type 2 diabetes and metabolic syndrome.

Background Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes. Methods We designed an in vitro assay using HEK-293 cell line transiently transfected with vectors containing the full ASCE or ASWT cDNAs. Progesterone or estradiol effects on AS enzyme activities were evaluated in transfected cells incubated with deoxycorticosterone (DOC) alone or DOC plus increasing doses of these steroids. Results In our in vitro model, both enzymes showed similar apparent kinetic parameters (Km = 1.191 microM and Vmax = 27.08 microM/24 h for ASCE and Km = 1.163 microM and Vmax = 36.98 microM/24 h for ASWT; p = ns, Mann–Whitney test). Progesterone inhibited aldosterone production by ASCE- and ASWT-transfected cells, while estradiol demonstrated no effect. Progesterone acted as a competitive inhibitor for both enzymes. Molecular modelling studies and binding affinity estimations indicate that progesterone might bind to the substrate site in both ASCE and ASWT, supporting the idea that this steroid could regulate these enzymatic activities and contribute to the decay of aldosterone synthase activity in chimeric gene-positive patients. Conclusions Our results show an inhibitory action of progesterone in the aldosterone synthesis by chimeric or wild type aldosterone synthase enzymes. This is a novel regulatory mechanism of progesterone action, which could be involved in protecting pregnant women with FH-1 against hypertension. In vitro, both enzymes showed comparable kinetic parameters, but ASWT was more strongly inhibited than ASCE. This study implicates a new role for progesterone in the regulation of aldosterone levels that could contribute, along with other factors, to the maintenance of an adequate aldosterone-progesterone balance in pregnancy.

BACKGROUND 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) inactivates cortisol (F) to cortisone (E); its impairment is associated with hypertension. We reported that 15.7% of the Chilean essential hypertensives possessed a high F/E ratio suggesting a partial deficit in 11β-HSD2 activity. It has been reported that the G534A(Glu178/Glu) polymorphism in the HSD11B2 gene is associated with hypertension. Investigate the frequency of the G534A polymorphism and its correlation with the glucocorticoid profile in Chilean essential hypertensive and normotensive subjects. METHODS Essential hypertensive outpatients (n = 232) and normotensive subjects (n = 74) were recruited. A change in the AluI restriction enzyme digest pattern, caused by the presence of the G534A polymorphism, was utilized to screen DNA isolated from leukocytes within the cohort before confirmation by sequencing. Plasma renin activity (PRA), serum aldosterone, F, and E were measured by radioimmunoassay. Urinary tetrahydrocortisol (THF), 5α-tetrahydrocortisol (5α-THF), and tetrahydrocortisone (THE) were measured by gas chromatography-mass spectrometry. RESULTS G534A polymorphism frequency was similar between hypertensive patients (19 of 232; 8.2%) and normotensive subjects (7 of 74; 9.5%). When categorized by presence or absence of the G534A polymorphism, no significant differences in the serum F/E ratio or other measured biochemical variables were detected. Despite a previous report that the G534A polymorphism is associated with a neighboring C468A (Thr156/Thr) polymorphism, analysis within our cohort showed that only one patient in each group presented with this double polymorphism. CONCLUSIONS We report the frequency of the G534A polymorphism in the Spanish-Amerindian population. No correlation was detected between this polymorphism and the presence of hypertension and biochemical parameters in this Chilean cohort.

Familial hyperaldosteronism type I is caused by an unequal crossover of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, giving rise to a chimeric CYP11B1/CYP11B2 gene (CG). We describe a family carrying a CG with high levels of free 18-hydroxycortisol but low prevalence of primary aldosteronism (PA) and an atypical CG inheritance pattern in a family of 4 generations with 16 adults and 13 children, we measured the arterial blood pressure, serum aldosterone, and plasma renin activity and then calculated the serum aldosterone:plasma renin activity ratio and urinary free 18-hydroxycortisol. We identified the CG by long-extension PCR and predicted its inheritance pattern. The CG was found in 24 of 29 subjects (10 children and 14 adults). In CG+ patients, hypertension and high 18-hydroxycortisol were prevalent (83% and 100%, respectively). High serum aldosterone:plasma renin activity ratio was more frequent in pediatric than adult patients (80% versus 36%; P r =−0.48; P =0.018). Sequence analysis identified the CYP11B1/CYP11B2 crossover in a 50-bp region spanning intron 3 of CYP11B1 and exon 4 of CYP11B2. The CG segregation differs from an autosomal disease, showing 100% of CG penetrance in generations II and III. Statistical analysis suggests that inheritance pattern was not attributed to random segregation ( P

Cortisol homeostasis is implicated in hypertension and metabolic syndrome. Two enzymes modulate cortisol availability; 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) preferentially converts inactive cortisone to cortisol, whereas 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts cortisol to cortisone. In contrast, 5α and 5β reductases inactivate cortisol by conversion to its tetrahydrometabolites: tetrahydrocortisol, allo-tetrahydrocortisol and tetrahydrocortisone. A subtle local increase in cortisol can be detected by measuring 24-h urine metabolites, LC–MS/MS being the reference method. The 11β-HSD2 activity is assessed based on the cortisol/cortisone ratio, and the 11β-HSD1 activity on the (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone ratio. To better understand hypertension and/or metabolic syndrome pathogenesis a method for simultaneous determination of cortisol, cortisone, tetrahydrocortisol, allo-tetrahydrocortisol and tetrahydrocortisone was developed and validated in an LC coupled with the new detector AB Sciex QTrap® 4500 tandem mass spectrometer. The steroids were extracted from 1 mL urine, using cortisol-D4 as internal standard. The quantification range was 0.1–120 ng/mL for cortisol and cortisone, and 1–120 ng/mL for tetrahydrometabolites, with >89 % recovery for all analytes. The coefficient of variation and accuracy was

Drug-drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the 'First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications'. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed., The project received funding from Novartis, Pfizer, Grunenthal, Esteve and Kyowa Hakko Kirin; none of the funding bodies participated in the workshop discussion. The authors would like to thank i2e3 research institute for providing editorial assistance on behalf of SOLTI.