Uptake of Risk-Reducing Measures, Cascade Testing, and Related Challenges Among Carriers of Breast Cancer-Associated Germline Pathogenic Variants in Mexico.

PURPOSE: Genetic cancer risk assessment (GCRA) provides pathogenic variant (PV) carriers with the invaluable opportunity to undertake timely cancer risk-reducing (RR) measures and initiate cascade testing (CT). This study describes the uptake of these strategies and the related barriers among breast cancer-associated germline PV carriers in Mexico. METHODS: Carriers who were at least 6 months after disclosure of genetic test results at two GCRA referral centers were invited to answer a survey assessing sociodemographic characteristics, awareness of their carrier status and its implications, uptake of RR measures according to international guidelines by PV, CT initiation, and associated challenges. RESULTS: Of the eligible carriers, 246/384 (64%) answered the survey (median age: 44 years). Most were female (88%), married/in domestic partnership (66%), and had personal breast/ovarian cancer history (61%). PVs included BRCA1/2 (75%), CHEK2 (10%), PALB2 (5%), ATM (5%), NF1 (2%), RAD51C (2%), PTEN (1%), and TP53 (1%). Most (87%) participants were aware of their carrier status. When recommended, 37% underwent RR bilateral mastectomy, 48% RR oophorectomy, 70% annual mammogram, and 20% breast magnetic resonance imaging. Challenges hindering the uptake of RR measures included financial limitations (67%), lack of recommendation by their physician (35%), and fear (24%). Nearly all (98%) claimed sharing their results with their relatives. CT was initiated in 63% of families and was associated with carriers being married/in domestic partnership (P = .04) and believing GCRA was useful (P < .001). CONCLUSION: Despite the resource-constrained setting, relevant rates of RR measures and CT were observed. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients' understanding on carrier status are warranted to enhance the overall benefit of GCRA and ultimately improve the provision of patient-centered care to both carriers and their at-risk relatives.

Germline DNA Repair Genes Pathogenic Variants Among Mexican Patients With Prostate Cancer.

BACKGROUND: Early identification of germline mutation carriers may be relevant for the optimal management of prostate cancer and to inform cancer risk in relatives. However, population minorities have limited access to genetic testing. The aim of this study was to describe the frequency of DNA repair gene pathogenic variants (PVs) among Mexican men with prostate cancer referred for Genomic Cancer Risk Assessment and testing. METHODS: Patients diagnosed with prostate cancer who meet criteria for genetic testing and enrolled in the Clinical Cancer Genomics Community Research Network at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City were included. Descriptive statistics were performed using frequency and proportions for categorical variables and median and range for quantitative variables. X2 and t test were used for group comparisons. RESULTS: A total of 199 men were enrolled, median age at diagnosis was 66 (range 44-88) years; 45% were de novo metastatic and 44% were high- very high and 10% were intermediate risk group. Four (2%) had a pathogenic germline variant; one each of the following genes: ATM, CHEK2, BRIP1, and MUTYH (all monoallelic). Younger men at diagnosis were more likely to carry a PV than older age at diagnosis (56.7 vs. 66.4 years, P = .01). CONCLUSION: Our results showed a low prevalence of known prostate cancer associated PVs and no BRCA PVs in Mexican men with prostate cancer. This suggests that the genetic and/or epidemiologic risk factors for prostate cancer are not well characterized in this specific population.

Reference levels for 17-hydroxyprogesterone, 11-desoxycortisol, cortisol, testosterone, dehydroepiandrosterone sulfate and androstenedione in infants from birth to six months of age.

Reference plasma adrenal steroid levels during early infancy are frequently used to verify hormone measurements when any adrenal abnormality is suspected. We aim to obtain longitudinal reference plasma levels for 17-hydroxyprogesterone (17OHP), 11-desoxycortisol (11DOC), cortisol, dehydroepiandrosterone sulfate (DHEAS), testosterone, and androstenedione in healthy infants from birth to 6 months of age. In 138 term infants, 80 males and 58 females, plasma steroid levels were measured using specific RIA procedures at birth and on the 3rd, 15th, 30th, 60th, 90th, 120th, 150th, and 180th days of life. Smoothed percentiles for each variable were calculated according to the LMS method (LMS program version 1.16, Institute of Child Health, London). Except for cortisol, plasma levels of adrenal steroids decreased progressively from birth to 6 months of age. Plasma concentrations of 17OHP, 11DOC, and cortisol did not show gender differences, but testosterone and androstenedione were significantly higher in boys, and DHEAS levels were higher in girls. Longitudinal reference plasma levels for 17OHP, 11DOC, cortisol, DHEAS, testosterone, and androstenedione have been described in an adequate sample of healthy infants from birth to 6 months of age. These standards, displayed as smoothed percentiles, may be used as reference values in the management of congenital endocrine (adrenal or gonadal) abnormalities that appear in the first weeks of life.

Screening performances of the International Obesity Task Force body mass index cut-off values in adolescents.

OBJECTIVE: To try to improve the International Obesity Task Force (IOTF) BMI cut-off values, in terms of prediction of body fat percentage assessed by dual-energy X-ray absorptiometry (DXA), in adolescents. METHODS: Cross-sectional survey of the adolescents from the city of Zaragoza (Spain). For this analysis we have included 286 adolescents (116 boys and 170 girls) aged 13.0-17.9 years. Body mass index (BMI) was calculated as body weight (kg), divided by height (m) squared. The percentage of body fat (BF%) was estimated by the use of DXA. RESULTS: We have calculated, new BMI cut-off values (AVENA cut-offs) to predict BF%, for boys and girls in each age group. In male adolescents, sensitivity was higher with the IOTF cut-offs (0.71, 95th C.I.: 0.44, 0.90) than with the AVENA ones (0.53, 95th C.I.: 0.28, 0.77), and specificity was very similar with both cut-off values (0.86 and 0.88, respectively), the differences being not statistically significant. In girls, both sensitivities (0.75 and 0.79, respectively) and specificities (0.90 and 0.92, respectively) were very similar with both cut-off values, and the differences, not significant. CONCLUSIONS: Optimization of the IOTF BMI cut-off values, in terms of BF%, seems not to be possible in adolescents. The IOTF criteria should be used only for overweight and obesity screening; however, in clinical settings, a more accurate measure of body fat should be recommended.

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.

Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype-phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.2, including ALX4. We explored the correlations between skull defect size and age, gene, and mutation type, and reviewed additional phenotypic manifestations. Four PFM cases had mutations in either ALX4 or MSX2; including previous families, we have identified six ALX4 and six MSX2 mutations, accounting for 11/13 familial, but only 1/6 sporadic cases. The deletion family confirms the delineation of a mental retardation locus to within 1.1 Mb region of 11p11.2. Overall, no significant size difference was found between ALX4- and MSX2-related skull defects, but the ALX4 mutation p.R218Q tends to result in persistent CB and is associated with anatomical abnormalities of the posterior fossa. We conclude that PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable. Mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.

Cardiac findings in adolescents with anorexia nervosa at diagnosis and after weight restoration.

UNLABELLED: The aim of this study was to compare heart abnormalities in a group of young women with anorexia nervosa at diagnosis and after weight restoration. A total of 40 young women with anorexia nervosa were evaluated, at baseline, (diagnosis) and follow-up (9 to 18 months later) and matched with 40 healthy women of the same age and of normal weight. QT interval was measured from surface electrocardiograms. QT dispersion was defined as the difference between maximum QT and minimum QT occurring in any of the 12 leads. Left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left ventricular mass, left ventricular mass index, cardiac output, fractional shortening and fractional ejection, were measured by echocardiography. In anorexia nervosa patients, corrected QT interval and QT dispersion, significantly decreased from baseline to follow-up. Left ventricular end-diastolic dimension, left ventricular mass index, and cardiac output, in anorexia nervosa were significantly lower at diagnosis than at follow-up after weight restoration. CONCLUSION: Adolescents with anorexia nervosa have significant functional and structural cardiac abnormalities; weight gain was associated with improvement. Appropriate attention should be paid to cardiac involvement.

Electrocardiographic and echocardiographic findings in malnourished children.

OBJECTIVE: To compare heart abnormalities in a group of malnourished children with a control group and to describe their predictive variables. METHODS: Thirty children with malnutrition were matched with thirty healthy children. Anthropometry, plasma levels of albumin and electrolytes were determined. Among others, corrected QT interval (QTc) and QT dispersion (QTd: difference between the maximum and the minimum QT) were measured in 12-lead electrocardiogram; and left ventricular mass (LVm) and left ventricular mass index (LVmi) were measured by echocardiography. Regression analyses were performed with cardiac findings as dependent variables and anthropometric and biochemical data as independent variables. RESULTS: Plasma levels of albumin, potassium and calcium were lower in malnourished children. QTc and QTd were significantly greater in patients with malnutrition than in controls (QTc: 445.9 +/- 31.4 vs. 400.9 +/- 17.7 ms, p = 0.000; QTd: 76.4 +/- 34.1 vs. 47.9 +/- 10.2 ms, p = 0.000). LVm and LVmi were significantly lower in malnourished children (LVm: 55.3 +/- 10.3 vs. 71.4 +/- 6.9 g, p = 0.000; LVmi: 46.5 +/- 6.6 vs. 60.5 +/- 4.9 g/m2, p = 0.000). The body mass index (kg/m2) was the most powerful predictor of the variability in QTc (39.1%), LVm (48.1%) and LVmi (51.2%). CONCLUSIONS: Important electrocardiographic and echocardiographic abnormalities have been found in malnourished children associated with their nutritional status. Special precaution must be taken about the possibility of occurrence of arrhythmias and sudden death related with malnutrition.

Mechanical resistance of a new biomaterial, ostrich pericardium, and a new method of joining tissues combining suturing and a biological adhesive.

We studied the mechanical behavior in response to tensile stress of samples of ostrich pericardium bonded with a cyanoacrylate glue or sewn with a rectangular, overlapping suture that was subsequently sealed with the same bioadhesive. Seventy-two trials were performed in three series of 24 samples each: series AG, glued with an overlap of 1 cm2; series ASG, sewn with a rectangular, overlapping suture and sealed; and series AC, control samples that were left intact. The mean stress at rupture in series AG (glued) was 0.1 MPa, much lower than the working stress of a human valve leaflet, which is approximately 0.25 MPa. In the control series, this stress was 26.28 MPa. At rupture in series ASG (sutured/glued), the suture material was being subjected to a stress of 64.91 MPa, thus confirming the existence of an interaction between the suture and the shear stress exerted by the suture on the samples of pericardium. In series ASG, the mean value for the resistance to rupture when measured in machine kg was 8.83 kg, lower than but similar to that recorded in the control series AC (10.26 kg). The percentages of reversible deformation, or elongation, once the samples were torn were similar in series AC (19.15%) and ASG (21.93%). This phenomenon can only be explained by the damage to the collagen fibers in the area around the rupture, while other more distant regions work at a lower load within the elastic limit. We conclude that cyanocrylate adhesives alone are not suitable as bonding materials in cardiac bioprostheses. The results with the rectangular, overlapping suture, when subsequently sealed with an adhesive, can be considered good because, although this approach does not impede shear stress, it does maintain an excellent degree of resistance to rupture of the samples thus joined. We stress the need to take into account the concentration of the load in the design of bioprostheses.

Gender differences in newborn subcutaneous fat distribution.

UNLABELLED: The pattern and distribution of subcutaneous fat in term and preterm newborns has been assessed by skinfold thicknesses (ST), describing gender and gestational age variations. Weight, length and ST (triceps, biceps, subscapular and suprailiac) were measured in 4634 neonates (2445 males and 2189 females) aged from 32 to 41 gestational weeks. Central to total skinfold ratio (CTS), (suprailiac + subscapular)/sum of 4 ST, was calculated. Males were heavier and longer than females. The sum of 4 ST and CTS was higher in females at every gestational age (with significant differences from 35 weeks) and also the sum of 4 ST per kg body weight (P < 0.05 from 32-33 weeks). Throughout the gestational period, ST increased significantly (P < 0.0001) but CTS did not show variations, neither in males nor in females. CONCLUSION: term and preterm females have a more centralised pattern and more amount of subcutaneous fat than males. Central to total skinfold ratio must be considered as an index of centripetal fat store which is independant of gestational age.

Inhaled nitric oxide affects endogenous surfactant in experimental lung transplantation.

BACKGROUND: Inhalation of nitric oxide (NO) has been proposed as a therapy to improve lung transplantation outcome. We investigated the effect that inhaled NO has on the surfactant system in the context of ischemia-reperfusion injury. METHODS: Single left-lung transplantation was performed in weight-matched pairs of Landrace pigs. A double-lung block from the donor animal was flushed with University of Wisconsin solution at 4 degrees C followed by immersion in cold University of Wisconsin solution for 22 hr. The left donor lung was transplanted into the recipient. Recipients were divided into two groups: (1) treated with inhaled NO (40 ppm) (n=6) immediately after initiating lung reperfusion and (2) without treatment (n=6). Lung function was measured during 2 hr of reperfusion. Surfactant components in small and large aggregates, isolated from cell-free bronchoalveolar lavages, and surfactant function were measured. RESULTS: NO inhalation significantly decreased arterial oxygenation. With respect to the surfactant system, NO inhalation worsened the surfactant adsorption rate to an air-liquid interface and affected levels of hydrophobic surfactant proteins (SPs), SP-B and SP-C, and phospholipids, which decreased in large surfactant aggregates but not in small surfactant aggregates. SP-A was reduced in large surfactant aggregates of transplanted lungs from both untreated and NO-treated groups. CONCLUSION: A decreased level of SP-A, SP-B, and SP-C in large surfactant aggregates of transplanted lungs treated with NO is a marker of lung injury. We conclude that treatment with inhaled NO after lung transplantation is deleterious for the surfactant system and causes a parallel worsening of arterial oxygenation.

El prolapso de la válvula mitral es una alteración cardiovascular frecuente en los pacientes con anorexia nerviosa. Respuesta / Mitral valve prolapse is a frequent cardiovascular finding in patients with anorexia nervosa. Response

No disponible

Serum mineral levels in children with intestinal parasitic infection.

Parasitic infections are highly prevalent in the general population. A relation between a parasitic infection and absorption of minerals is not an easy task. Serum levels of copper, zinc and magnesium were prospectively measured in 64 children with intestinal parasitic infection. Thirty-nine children with Enterobius vermicularis were treated with pyrantel pamoate and 25 children with Giardia lamblia with tinidazole and metronidazole. Three months after treatment, significant differences in serum copper, zinc and magnesium were seen in patients with E. vermicularis infection, and in serum magnesium levels in patients with G. lamblia. Although the pathogenic mechanism is not clear, these findings could reflect a deficiency related to malabsorption due to mucous affection. Early detection and treatment of intestinal parasitosis could avoid these serum mineral deficiencies.

[Cardiac disorders in young women with anorexia nervosa]. / Alteraciones cardiológicas en mujeres adolescentes con anorexia nerviosa.

INTRODUCTION AND OBJECTIVES: The objective of this study was to compare heart abnormalities in young women with anorexia nervosa and in a control group of the same age and sex. Patients and method. We report a matched case-control study of 30 adolescents with anorexia nervosa and 30 healthy women of the same age with normal weight. An electrocardiogram and echocardiogram were done. Heart parameters were measured on the electrocardiographic tracings, and QT dispersion was defined as the difference between maximum QT and minimum QT in any of the 12 leads. Diameter, mass and left ventricular mass index were measured. RESULTS: QT and corrected QT intervals were significantly greater in patients with anorexia nervosa than in the control group. QT dispersion and corrected QT dispersion were significantly greater in anorexia nervosa than in the control group (QTd, 59.3 23.0 vs 38.4 8.0 ms; p = 0.000; QTcd, 56.5 24.2 vs. 40.3 21.8 ms; p = 0.011). Left ventricular mass was significantly lower in young women with anorexia nervosa. We found a significant relationship between body mass index and left ventricular mass index, and between the former and corrected QT dispersion. CONCLUSIONS: Adolescents with anorexia nervosa show significant cardiac disorders in comparison to healthy women of the same age. This finding may be a useful indicator of the risk of arrhythmia and sudden death in patients with anorexia nervosa.

Alteraciones cardiológicas en mujeres adolescentes con anorexia nerviosa / Cardiac disorders in young women with anorexia nervosa

Introducción y objetivos. El objetivo de este estudio es comparar las alteraciones cardiológicas de mujeres adolescentes con anorexia nerviosa con un grupo control de la misma edad y sexo. Pacientes y método. Se trata de un estudio de casos y controles apareado en 30 mujeres adolescentes con anorexia nerviosa y 30 controles sanas de la misma edad y peso normal. Se les realizó electrocardiograma y ecocardiograma. Los parámetros cardiológicos fueron medidos sobre la superficie de los electrocardiogramas y la dispersión de QT fue definida como la diferencia entre el máximo y el mínimo QT de las 12 derivaciones. Se cuantificó el diámetro y la masa y el índice masa del ventrículo izquierdo. Resultados. Los intervalos QT y QT corregidos fueron significativamente mayores en pacientes con anorexia nerviosa que en el grupo control. Las dispersiones del intervalo QT y del intervalo QT corregido fueron significativamente mayores en la anorexia nerviosa que en el grupo control (QTd, 59,3 ñ 23,0 frente a 38,4 ñ 8,0 ms; p = 0,000; QTcd, 56,5 ñ 24,2 frente a 40,3 ñ 21,8 ms; p = 0,011). La masa del ventrículo izquierdo fue significativamente menor en las mujeres con anorexia nerviosa. Existe una correlación significativa entre el índice de masa corporal y el índice de masa del ventrículo izquierdo y la dispersión del intervalo QT corregido. Conclusiones. Las adolescentes con anorexia nerviosa presentan alteraciones cardiológicas significativas en relación con mujeres sanas de la misma edad. Dichos parámetros pueden ser indicadores útiles de riesgo de arritmia y muerte súbita en pacientes con anorexia nerviosa (AU)

Autoimmune thyroiditis after bone marrow transplantation in a boy with Wiskott-Aldrich syndrome.

We report a boy with Wiskott-Aldrich syndrome (WAS) who developed autoimmune thyroiditis 19 months after allogenic bone marrow transplantation (BMT). Possible causes of his autoimmune illness were 1) transference of autoimmune cells from the donor, which was ruled out because of the absence of autoimmune illness in his healthy HLA-identical brother (donor); 2) persistent mixed chimerism after BMT ruled out by post-BMT molecular analysis of the proband's peripheral lymphocytes; and 3) patient's predisposition to autoimmune disease secondary to an dysregulated immune system because of WAS and his HLA haplotype. This case brings previously unreported findings to the spectrum of WAS.

Vitamin B12 and folic acid in children with intestinal parasitic infection.

OBJECTIVE: To determine prospectively plasma levels of vitamin B12 and folic acid in children with intestinal parasitic infection before and three months after antiparasitic treatment. METHODS: 3036 stool samples were collected from 1959 children and 939 cello-tape anal swabs were taken from 688 children for intestinal parasite investigation. Of these, 155 children were identified as having a parasitic infection; however, only 86 were followed up during this study: 26 children with Giardia lamblia infection were treated with tinidazole and metronidazole, pyrantel pamoate was used in the treatment of 40 children with Enterobius vermicularis, and 20 patients infected with Cryptosporidium parvum received only symptomatic treatment. Vitamin B12 and folic acid levels were measured by radioimmunoassay, before and three months after the completion of treatment. RESULTS: Vitamin B12 serum concentrations did not show any significant differences among the three groups. There was a significant increase in vitamin B12 serum concentrations after three months of anti-parasitic treatment (630.57+/-200.97 vs. 667.97+/-181.55 pg/dL, p = 0.002, n = 86). Paired analysis in each group showed only significant increases for vitamin B12 in the Giardia lamblia group and in the Enterobius vermicularis group. No statistically significant differences were found for folic acid serum concentrations before and three months after treatment. CONCLUSIONS: Patients with symptomatic infection by Giardia lamblia and Enterobius vermicularis have lower vitamin B12 levels than asymptomatic patients. This could reflect a more affected intestinal mucous. These results could present the opportunity to treat these parasitic infections and to use vitamin B12 supplementation in symptomatic children with Giardia lamblia and Enterobius vermicularis infection.