Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Exploring the Effects of Mitonuclear Interactions on Mitochondrial DNA Gene Expression in Humans.

Most mitochondrial protein complexes include both nuclear and mitochondrial gene products, which coevolved to work together. This coevolution can be disrupted due to disparity in genetic ancestry between the nuclear and mitochondrial genomes in recently admixed populations. Such mitonuclear DNA discordance might result in phenotypic effects. Several nuclear-encoded proteins regulate expression of mitochondrial DNA (mtDNA) genes. We hypothesized that mitonuclear DNA discordance affects expression of genes encoded by mtDNA. To test this, we utilized the data from the GTEx project, which contains expression levels for ∼100 African Americans and >600 European Americans. The varying proportion of African and European ancestry in recently admixed African Americans provides a range of mitonuclear discordance values, which can be correlated with mtDNA gene expression levels (adjusted for age and ischemic time). In contrast, European Americans did not undergo recent admixture. We demonstrated that, for most mtDNA protein-coding genes, expression levels in energetically-demanding tissues were lower in African Americans than in European Americans. Furthermore, gene expression levels were lower in individuals with higher mitonuclear discordance, independent of population. Moreover, we found a negative correlation between mtDNA gene expression and mitonuclear discordance. In African Americans, the average value of African ancestry was higher for nuclear-encoded mitochondrial than non-mitochondrial genes, facilitating a match in ancestry with the mtDNA and more optimal interactions. These results represent an example of a phenotypic effect of mitonuclear discordance on human admixed populations, and have potential biomedical applications.

Cystathionine ß-synthase and methylenetetrahydrofolate reductase mutations in Mexican individuals with hyperhomocysteinemia.

BACKGROUND: Hyperhomocysteinemia, a thrombotic risk factor, may have several causes. Among the genetic causes of hyperhomocysteinemia, there are polymorphisms in the enzymes methylenetetrahydrofolate reductase (C677T) and cystathionine ß-synthase (C699T, C1080T, and 844ins68). Although the frequency of hyperhomocysteinemia in our country is high, there is no evidence about the frequencies of these polymorphisms. METHODS: We analyzed 80 healthy individuals from several regions in our country. We evaluated the fasting and post-oral methionine load plasma Hcy and the genotypes in order to obtain the allele frequencies of the polymorphisms C677T of methylenetetrahydrofolate reductase and C699T, C1080T, and 844ins68 of the cystathionine ß-synthase. RESULTS: No individual had deficiency of folic acid, vitamins B12, or B6, but 80% had post-oral methionine load hyperhomocysteinemia. We found a significant increase in the Hcy plasma concentration associated with age and gender. Only the polymorphism C1080T was significantly associated with hyperhomocysteinemia. CONCLUSION: There is an association between fasting and post-oral methionine load plasma Hcy concentrations with the allelic frequencies of the polymorphisms C669T, 844ins68, and C1080T of the cystathionine ß-synthase and C667T of the methylenetetrahydrofolate reductase in healthy Mexican individuals. As compared with individuals with normal fasting or post-oral methionine load Hcy plasma levels, only C1080T was significantly associated with hyperhomocysteinemia.

The D2 and D3 Sublineages of Human Papilloma Virus 16-Positive Cervical Cancer in Guatemala Differ in Integration Rate and Age of Diagnosis.

Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, and D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 65% (62/96) of the samples had integrated HPV16 sequences and integration was associated with an earlier age of diagnosis and premenopausal disease. HPV16 integration sites were broadly distributed in the genome, but in one tumor, HPV16 integrated into the promoter of the IFN regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the IFN response to viral infection. The HPV16 D2 and D3 sublineages were found in 23% and 30% of the tumors, respectively, and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration, earlier age of diagnosis, and a lower rate of somatic mutation, whereas D3-positive tumors were less likely to integrate, had later age of diagnosis, and exhibited a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of very high-risk HPV16 D2 and D3 sublineages harboring distinct histology, which may help guide future therapeutic strategies to target the tumor and reduce recurrence. SIGNIFICANCE: This study details the biological and molecular properties of the most pathogenic forms of HPV16, the cause of the majority of cervical cancers.

Oxidative damage and antioxidant defense in thymus of malnourished lactating rats.

OBJECTIVE: Malnutrition has been associated with oxidative damage by altered antioxidant protection mechanisms. Specifically, the aim of this study was to evaluate oxidative damage (DNA and lipid) and antioxidant status (superoxide dismutase [SOD], glutathione peroxidase [GPx], and catalase [CAT] mRNA, and protein expression) in thymus from malnourished rat pups. METHODS: Malnutrition was induced during the lactation period by the food competition method. Oxidative DNA damage was determined quantifying 8-oxo-7, 8-dihydro-2'-deoxyguanosine adduct by high-performance liquid chromatography. Lipid peroxidation was assessed by the formation of thiobarbituric acid-reactive substances. Levels of gene and protein expression of SOD, GPx, and CAT were evaluated by real-time polymerase chain reaction and Western blot, respectively. Antioxidant enzyme activities were measured spectrophotometrically. RESULTS: Oxidative DNA damage and lipid peroxidation significantly increased in second-degree (MN-2) and third-degree malnourished (MN-3) rats compared with well-nourished rats. Higher amounts of oxidative damage, lower mRNA expression, and lower relative concentrations of protein, as well as decreased antioxidant activity of SOD, GPx, and CAT were associated with the MN-2 and MN-3 groups. CONCLUSIONS: The results of this study demonstrated that higher body-weight deficits were related to alterations in antioxidant protection, which contribute to increased levels of damage in the thymus. To our knowledge, this study demonstrated for the first time that early in life, malnutrition leads to increased DNA and lipid oxidative damage, attributable to damaged antioxidant mechanisms including transcriptional and enzymatic activity alterations. These findings may contribute to the elucidation of the causes of previously reported thymus dysfunction, and might explain partially why children and adults who have overcome child undernourishment experience immunologic deficiencies.

Cardiotoxicidad por Antraciclinas. Presentación de un caso / Anthracycline-induced cardiotoxicity. A case presentation

Se presenta un caso atendido en el Hospital Provincial Docente “Dr. Antonio Luaces Iraola” de Ciego de Ávila, que por su poca frecuencia se considera importante su exposición. Una mujer de 54 años con lesión en el paladar, de gran tamaño, redondeada, de superficie dura e irregular, a la que se le realizan estudios y se diagnóstica un Linfoma no Hodgkin bien diferenciado. Se brinda tratamiento con esquema de quimioterapia de 8 ciclos cada 21 días; al séptimo ciclo, con una dosis acumulada de adriamicina de 660mg/m2; comienza a presentar disnea al hacer grandes esfuerzos, se fue agravando su condición clínica y llega al Hospital con un edema agudo de pulmón; se le realizan estudios clínicos. Se concluye el caso con el diagnóstico de miocardiopatía dilatada (AU)

A case attended in the “Dr. Antonio Luaces Iraola” Provincial Hospital of Ciego de Avila is presented, that it considers important for its little frequency. A 54-year-old woman with injury in the palate, of big size, rounded, of hard and irregular surface, to which some studies are carried out and it diagnosed to her a quite differentiated Non-Hodgkin Lymphoma. It offers chemotherapy treatment of 8 cycles every 21 days, to 7th cycle with an accumulate dose of doxorubicin 660mg/m2, begins with dyspnea to the big efforts, its clinical condition was worsening and she arrives to the Hospital with an acute pulmonary edema, clinical studies were carried out . The case is concluded with dilated cardiomyopathy diagnosis (AU)

Maternal fetal transmission of Trypanosoma cruzi: a problem of public health little studied in Mexico.

The first case of neonatal Chagas was reported in Mexico in 1998, but there have been no studies since then. Therefore, we investigated the rates of congenital infection of Trypanosoma cruzi by examining the seroprevalence among 1448 pregnant women in Oaxaca, Jalisco and Mexico City. We performed ELISAs to screen for recombinant and total antigens in mothers, and examined the frequency of congenital T. cruzi transmission by PCR with cord blood and antibody testing in children when they reached two years old. Our results showed that the prevalence of infection in pregnant women was 7.32% (106/1448) overall, and 4.4% (35/794) in Oaxaca, 12.02% (67/557) in Jalisco and 4.12% (4/97) in the Mexico City. In Oaxaca, T. cruzi infection was detected by PCR in 20% (7/35) of infants born to seroreactive mothers and 11.9% (8/67) in Jalisco. No infections were identified in infants from the Mexico City. From these only eleven serological follow up their children are agree to take blood. Therefore, the maternal-fetal overall transmission rate was 4.08% (4/98) in Oaxaca and 9.1% (3/33) in Jalisco 1.5% (1/65) children with positive serology were given specific treatment Chagas. In conclusion, these are the first reports of the rates of congenital Chagas disease in Mexico. The seroprevalence was higher in mothers from Jalisco, and could be related to that there is not the periodic fumigation of the transmitting vector performed in that state. The high rates of maternal-fetal transmission found in Oaxaca could be related to the differences of pathogenicity of trypanosome. No association between both the rate of congenital transmission and the gynecologic anthropometric data was observed.

Anomalía de Ebstein y embarazo: presentación de 2 casos / Ebstein anomaly and pregnancy: two cases report

La enfermedad de Ebstein es una rara malformación cardiaca descrita por Wilhelm Ebstein en 1866 de la cual existen pocos reportes, se caracteriza por el desplazamiento apical de las valvas septal y posterior de la válvula tricúspide hacia el interior del ventrículo derecho, estas alteraciones determinan la auriculización de la porción basal del ventrículo derecho. Se presentan dos casos de embarazadas con esta malformación y la manifestación de insuficiencia cardiaca las llevó al departamento de Eco cardiografía del Centro Médico Diagnóstico de alta Tecnología José Martí, de la misión Barrio Adentro II, en la ciudad de Barcelona, estado Anzoátegui, República de Venezuela (AU)

Ebstein's anomaly is a rare cardiac malformation described by Wilhelm Ebstein in 1866 of which there are few reports, is characterized by apical displacement of septal and psterior leaflets of the tricuspid valve into the right ventricle, these alterations determine atrialization basal portion of the right ventricle. Two cases of pregnant women with this malformation are presented and the manifestation of heart failure led them to the echocardiography Department of Diagnostic Medical Center High Technology José Martí, Mission Barrio Adentro II, in Barcelona city, Anzoátegui state, Republic of Venezuela(AU)

Anomalía de Ebstein y embarazo: presentación de 2 casos / Ebstein anomaly and pregnancy: two cases report

La enfermedad de Ebstein es una rara malformación cardiaca descrita por Wilhelm Ebstein en 1866 de la cual existen pocos reportes, se caracteriza por el desplazamiento apical de las valvas septal y posterior de la válvula tricúspide hacia el interior del ventrículo derecho, estas alteraciones determinan la auriculización de la porción basal del ventrículo derecho. Se presentan dos casos de embarazadas con esta malformación y la manifestación de insuficiencia cardiaca las llevó al departamento de Eco cardiografía del Centro Médico Diagnóstico de alta Tecnología José Martí, de la misión Barrio Adentro II, en la ciudad de Barcelona, estado Anzoátegui, República de Venezuela.

Ebstein's anomaly is a rare cardiac malformation described by Wilhelm Ebstein in 1866 of which there are few reports, is characterized by apical displacement of septal and psterior leaflets of the tricuspid valve into the right ventricle, these alterations determine atrialization basal portion of the right ventricle. Two cases of pregnant women with this malformation are presented and the manifestation of heart failure led them to the echocardiography Department of Diagnostic Medical Center High Technology José Martí, Mission Barrio Adentro II, in Barcelona city, Anzoátegui state, Republic of Venezuela.

Validation of a Mexican Spanish version of the Children's Dermatology Life Quality Index.

The Children's Dermatology Quality Index was developed as a tool to evaluate the quality-of-life in children with skin diseases. While a useful, self-administered scale, it has not been validated in Spanish for Mexican children. The aim of this study was to validate a Mexican version. Direct English-Spanish translation of the Children's Dermatology Quality Index was performed by two translators, and a single version was produced by a consensus of experts. Clarity was tested in a cohort of 60 healthy children. A reverse English-Spanish translation was performed. In a second stage, the quality-of-life was evaluated in a cohort of 64 pediatric patients with atopic dermatitis using the SCOring Atopic Dermatitis Index and COOP-Dartmouth questionnaires, and its severity evaluated with SCOring Atopic Dermatitis Index. Sixty-four patients (32 males), aged 11.8 +/- 2.9 years, with atopic dermatitis of 1 to 3 years of evolution were evaluated. The Mexican Spanish version of the Children's Dermatology Quality Index showed a high internal consistency (Cronbach's Alpha = 0.83; (CI(95%) = 0.76-0.88) and a high test-retest reliability (gamma(s) = 0.97, p < 0.001). A high correlation was observed between Children's Dermatology Quality Index and COOP-Dartmouth (gamma(s) = 0.97, p < 0.001) and moderate correlation with SCOring Atopic Dermatitis Index (gamma(s) = 0.53, p < 0.001). The Children's Dermatology Quality Index questionnaire in its Mexican Spanish version is valid and reliable for evaluating quality-of-life in Mexican pediatric patients with atopic dermatitis.

Síndrome KID: comunicación de un caso / KID syndrome: case report

El síndrome KID es una genodermatosis poco frecuente caracterizada por la asociación de queratitis vascularizante, lesiones cutáneas hiperqueratósicas y sordera neurosensorial (Keratitis-Ichthyosis-Deafness; KID). Los pacientes afectadas pueden también presentar alopecia cicatricial, distrofia ungueal y anomalías dentarias. Su base genética es la presencia de mutaciones en las conexina 26 o 30. La mutación espontánea del gen GJB2, que codifica la conexina 26 y mapea en el brazo largo del cromosoma 13 (13q11-q12), es la principal causa del síndrome KID. Se realiza la presentación de un caso debido a la baja incidencia de esta entidad nosológica.

KID syndrome is a rare genodermatosis characterized by the association of vascularizing keratitis, hyperkeratotic skin lesions and sensorineural hearing loss (Keratitis-Ichthyosis-Deafness; KID). Affected patients may also have cicatricial alopecia, nail dystrophy, and dental anomalies. Its genetic base consists of mutations in the connexin 26 or connexin 30. The spontaneous mutation of the gene GBJB2, encoding connexin 26 and mapping to the long arm of chromosome 13 (13q11-q12), is the main cause of KID syndrome. We present a case due to the low incidence of this nosological entity.

Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population.

There is a great deal of evidence that points to the association of the tumor necrosis factor-alpha (TNF-alpha) gene as a common genetic factor in the pathogenesis of diseases that are caused by inflammatory and/or autoimmune etiologies. Two single nucleotide polymorphisms (SNPs) identified in the TNF-alpha promoter region have been associated with disease susceptibility and severity. We investigated whether -308G/A and -238G/A TNF-alpha polymorphisms were associated with asthma, systemic lupus erythematosus (SLE), and juvenile rheumatoid arthritis (JRA) in a pediatric Mexican population. In a case-control study of 725 patients (asthma: 226, JRA: 171, and SLE: 328) and 400 control subjects, the participants were analyzed using the allelic discrimination technique. The genotype distribution of both TNF-alpha polymorphisms was in Hardy-Weinberg equilibrium in each group. However, there were significant differences in the allele frequency of TNF-alpha-308A between the patients and the healthy controls. This allele was detected in 2.9% of the controls, 6.0% of asthmatic and JRA patients (p = 0.002 and p = 0.0086), and 6.7% of SLE patients (p = 0.00049); statistical significance was maintained after ancestry stratification (asthma: p = 0.0143, JRA: p = 0.0083, and SLE: p = 0.0026). Stratification by gender showed that the risk for the -308A allele in asthma and JRA was greater in females (OR = 4.16, p = 0.0008 and OR = 4.4, p = 0.0002, respectively). The TNF-alpha -238A allele showed an association only with JRA in males (OR = 2.89, p = 0.004). These results support the concept that the TNF-alpha gene is a genetic risk factor for asthma, SLE, and JRA in the pediatric Mexican population.

Contributions of the different water sources to the Elqui river runoff (northern Chile) evaluated by H/O isotopes.

We present the results of an isotope (2H and 18O) and hydrogeochemical study in order to constrain the origin, recharge, and evolution of the surface and groundwater in the arid Andean realm of the Elqui watershed. The results of 2H and18O analyses of water samples obtained during our summer and winter campaigns indicate a generally meteoric origin of the river and spring waters of the watershed. The isotope signature of water of the Elqui river and its tributaries as well as that of groundwater in the coastal region fits the 2H-18O relation of delta2H =7.61delta18O+6.1. A relatively fast discharge and a quasi-closed catchment area can be asserted for water along the river flow path. The tributaries from the more arid coastal area, north of the Elqui river, differ in their isotopic signature due to evaporation and hydrochemically due to interactions with the strongly altered and fractured volcanic rocks of the basement. In the Andean zone, the18O-enriched hydrothermal spring of Baños del Toro exhibits the influence of water-rock interaction processes. The chemistry of the river water changes from sulphate- to chloride-rich along the river course from the high Andean mountains to the coast. The sulphate-rich character of these Andean waters reflects their passage through sulphide-rich rock massifs that were subjected to strong oxidation processes in the near superficial environment. This sulphate signature is enforced by past and present mining of precious metal epithermal deposits (e.g. those of El Indio-Tambo Au-Cu-As district), in which mineralised zones were developed during a series of Miocene magmatic-hydrothermal episodes in the Andean realm. Owing to the proximity of the lower Elqui river waters and its tributaries to the Pacific coast, the chloride character may be induced by agricultural and marine (sea spray, fog) sources. Generally, the main source of the Elqui river water is mainly attributed to surface runoff and less to contributions from the basement fractured aquifer.

Circular dichroism of pig and bovine lactadherins and their affinity for the pig zona pellucida.

We have purified and characterized pig and bovine milk lactadherins. Studies by circular dichroism spectroscopy indicate that the two proteins present a similar folding pattern. Results have been discussed in terms of their affinity for pig zona pellucida in order to use these proteins as analogs of pig sperm lactadherin in gamete studies.

Eficacia del levamisol en el tratamiento de niños con papilomatosis recurrente y refractaria a los tratamientos convencionales / Efectiveness of levamisole in the treatment of children with recurrent and refractory papillomatosis to conventional therapeutic measures

La finalidad de este estudio fue demostrar la utilidad del levamisol en el tratamiento de niños con papilomatosis recurrente o refractaria a los tratamientos convencionales. El diseño del estudio fue de ensayo terapéutico. Se incluyeron en el mismo ocho niños con edad promeio de 6.8 años con papilomatosis bucal, genital o perianal. Todos se habían sometido a tratamiento previo. Los ocho pacientes recibieron levamisol a dosis diarias de 2.5 mg por kilogramo de peso cuatro días a la semana, con duración total del tratamiento de dos a 22 meses. El control previo al tratamiento y subsecuente al mismo fue fotográfico y con citología hemática. Se considera que, de los ocho pacientes, seis tuvieron una reacción adecuada. En 33 por ciento de los pacientes las lesiones desaparecieron totalmente, en 50 por ciento la regresión fue de 75 por ciento, y en 16 por ciento la regresión de las lesiones fue de 50 por ciento al momento del corte. Se concluye que en niños el levamisol es útil para el tratamiento de la papilomatosis, y que se puede utilizar con seguridad

Carcinoma epidermoide del pene en un adolescente: informe de un caso / Carcinoma of the penis in adolescents: A report case

Se informa de un paciente masculino de 15 años de edad, no circuncidado, con deficiente higiene personal y sin antecedentes de vida sexual activa, con un tumor en el pene. La biopsia confirmó carcinoma bien diferenciado, invasor con metástasis a los ganglios linfáticos de la región inguinal. En el tejido de la biopsia se realizó la búsqueda de ADN del virus del papiloma humano tipos 8, 11, 12 y 16 por la reacción en cadena de la polimerasa, la cual fue negativa. Al paciente se le propuso penectomía la que rechazó. Se dio tratamiento paliativo con quimioterapia y radioterapia. Posteriormente presento necrosis total del pene con amputación espontánea. Este es el primer caso de carcinoma epidermoide del pene en un adolescente informado en la literatura latinoamericana