Frequent Promoter Hypermethylation of the APC and RASSF1A Tumour Suppressors in Parathyroid Tumours

BACKGROUND: Parathyroid adenomas constitute the most common entity in primary hyperparathyroidism, and although recent advances have been made regarding the underlying genetic cause of these lesions, very little data on epigenetic alterations in this tumour type exists. In this study, we have determined the levels of promoter methylation regarding the four tumour suppressor genes APC, RASSF1A, p16(INK4A) and RAR-beta in parathyroid adenomas. In addition, the levels of global methylation were assessed by analyzing LINE-1 repeats. METHODOLOGY/PRINCIPAL FINDINGS: The sample collection consisted of 55 parathyroid tumours with known HRPT2 and/or MEN1 genotypes. Using Pyrosequencing analysis, we demonstrate APC promoter 1A and RASSF1A promoter hypermethylation in the majority of parathyroid tumours (71% and 98%, respectively). Using TaqMan qRT-PCR, all tumours analyzed displayed lower RASSF1A mRNA expression and higher levels of total APC mRNA than normal parathyroid, the latter of which was largely conferred by augmented APC 1B transcription levels. Hypermethylation of p16(INK4A) was demonstrated in a single adenoma, whereas RAR-beta hypermethylation was not observed in any sample. Moreover, based on LINE-1 analyses, parathyroid tumours exhibited global methylation levels within the range of non-neoplastic parathyroid tissues. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that APC and RASSF1A promoter hypermethylation are common events in parathyroid tumours. While RASSF1A mRNA levels were found downregulated in all tumours investigated, APC gene expression was retained through APC 1B mRNA levels. These findings suggest the involvement of the Ras signaling pathway in parathyroid tumorigenesis. Additionally, in contrast to most other human cancers, parathyroid tumours were not characterized by global hypomethylation, as parathyroid tumours exhibited LINE-1 methylation levels similar to that of normal parathyroid tissues

Salivary gland dysfunction markers in type 2 diabetes mellitus patients

Background: Diabetes mellitus (DM) is a chronic disease of the carbohydrate metabolism that, when not rigorously controlled, compromises systemic and organ integrity, thereby causing renal diseases, blindness, neuropathy, arteriosclerosis, infections, and glandular dysfunction, including the salivary glands. The aim of this study was to determine the relationship between the qualitative and quantitative parameters of salivary alteration, which are indicators of salivary gland dysfunction, and the level of metabolic control of type 2 diabetes patients. Material and Methods: A convenience sample of 74 voluntary patients with type 2 DM was selected, each of whom donated a sample of unstimulated saliva. Salivary parameters such as salivary flow rate, protein concentration, pH, and xerostomia were studied. Results: There is a positive relationship between the level of metabolic control measured with HbA1 and the protein concentration in saliva (Spearman rho = 0.329 and p = 0.004). The same assay showed an inverse correlation between HbA1 and pH (Spearman rho = -0.225 and p = 0.05). Conclusions: The protein concentration in saliva and, to a lesser extent, the pH may be useful as glandular dysfunction indicators in DM2 patients

Alerta de incendios 2023-2024 para el noreste rionegrino

EEA Valle InferiorFil: Olmedo, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Villablanca, Mariana. Provincia de Río Negro. Ministerio de Producción y Agroindustria; ArgentinaFil: Devesa, Antonia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Alto Valle. Agencia de Extensión Río Colorado; ArgentinaFil: Marinzalta, Mauro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Valle Inferior; ArgentinaFil: Neira Zile, Fernanda. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Valle Inferior; ArgentinaFil: Aramburu, Manuela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Valle Inferior. Agencia Extensión Rural General Conesa; ArgentinaFil: Segura, Atilio Ramón. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Valle Inferior. Agencia Extensión Rural General Conesa; ArgentinaFil: Bueno Jorge Luis. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Valle Inferior. Agencia de Extensión Rural San Javier; ArgentinaFil: Leoni, Germán. Provincia de Río Negro. Ministerio de Agricultura; Argentin

PathogenMip Assay: A Multiplex Pathogen Detection Assay

The Molecular Inversion Probe (MIP) assay has been previously applied to a large-scale human SNP detection. Here we describe the PathogenMip Assay, a complete protocol for probe production and applied approaches to pathogen detection. We have demonstrated the utility of this assay with an initial set of 24 probes targeting the most clinically relevant HPV genotypes associated with cervical cancer progression. Probe construction was based on a novel, cost-effective, ligase-based protocol. The assay was validated by performing pyrosequencing and Microarray chip detection in parallel experiments. HPV plasmids were used to validate sensitivity and selectivity of the assay. In addition, 20 genomic DNA extracts from primary tumors were genotyped with the PathogenMip Assay results and were in 100% agreement with conventional sequencing using an L1-based HPV genotyping protocol. The PathogenMip Assay is a widely accessible protocol for producing and using highly discriminating probes, with experimentally validated results in pathogen genotyping, which could potentially be applied to the detection and characterization of any microbe

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Genetic background of familial primary hyperparathyroidism

In this thesis the aim has been to identify and characterise gene(s) involved in familial primary hyperparathyroidism (PHPT). In multiple endocrine neoplasia type 1 (MEN 1), the hyperparathyroidism-jaw tumour syndrome (HPT-JT) and familial isolated hyperparathyroidism (FIHP), in which primary hyperparathyroidism is seen in most or almost all gene carriers. In Finland monogenic disorders are known to cluster in specific regions. MEN1 mutation screening of Finnish MEN 1 families and isolated cases identified two mutations that were traced back to their respective founder couple by genealogical studies. It is therefore worthwhile to screen for these two mutations in new Finnish MEN 1 patients (Paper I). The diagnosis of FIHP relies on the exclusion of other familial forms of PHPT e.g. MEN 1 and HPT-JT. In an attempt to clarify the underlying cause of FIHP, the MEN1 gene and the HRPT2 gene locus were investigated by mutation screening, loss of heterozygosity (LOH) and comparative genomic hybridisation (CGH) studies. Four families were positive for MEN1 mutations. Two families have since then developed symptoms suggestive of MEN 1. Thus, genetic screening is important of FIHP families as it may predict disease and allow early detection and appropriate treatment (Paper II and III). Solitary parathyroid adenomas have been identified in most cases responsible for the PHPT in the HPT-JT related families. In addition, an over-representation of cystic features and increased risk of parathyroid carcinoma have been noted. We characterised clinically and genetically cystic parathyroid adenomas by LOH and immunohistochemistry. In addition, mutation screening was carried out of HRPT2 gene. A significant correlation between tumours with LOH and the clinical parameters such as tumour weight and PTH was found (Paper IV). Three somatic inactivating mutations were identified in the HRTP2 gene implicating its role as a tumour suppressor gene (TSG) and the involvement in the tumourigenesis in a subset of sporadic parathyroid tumours (Paper V). Using a positional cloning approach, we report the identification of a disease gene for the hyperparathyroidismjaw tumour syndrome (HPT-JT). A combined genotyping study followed by mutation analysis of candidate genes in the critical interval revealed thirteen different heterozygous, germline mutations in a single gene in fourteen HPT-JT kindreds. HRPT2 (1q25) is a tumour suppressor gene consisting of 17 coding exons with a predicted protein of 531 amino acids, termed parafibromin. (Paper V). The genetic background of FIHP has been considered heterogeneous as many of the reported families have been assigned to the different loci such as the MEN1 and HRPT2. To ftirther elucidate the genetics underlying FIHP, we screened the HRPT2 gene for mutations. We identified four novel HRPT2 mutations and describe for the first time its involvement in FIHP (Paper VI). The HRPT2 gene is evolutionarily conserved and widely expressed. To further characterize HRPT2, we raised an antibody against the encoded protein, parafibromin. By expression studies such as Western blot and immunohistochemistry, a protein of approximately 60kD was revealed in relevant tissues examined and predominantly localized to the cytosol. These findings suggest a cytoplasmatic function for this protein (Paper VII)

Función sexual en estudiantes universitarias

Objetivo: Describir la función sexual en estudiantes universitarias pertenecientes a universidades de Chillán, Chile. Métodos: Diseño cuantitativo, descriptivo, transversal, que incluyó 220 mujeres universitarias con rango etario entre 17 a 40 años que cumplían con los criterios de selección. La información se recopiló mediante un Google cuestionario, debido ala contingencia sanitaria por la COVID-19. Se incluyeron variables sociodemográficas, además de encuestas sobre orgasmo femenino e Índice de Función Sexual Femenina. Resultados: Con respecto a los ítems del Índice de Función Sexual Femenina, se observaron puntajes que indican rangos de normalidad en todos los dominios, aunque algunos con puntajes muy cercanos a los de corte. Sobre índices de excitación, lubricación, orgasmo y dolor con puntaje de corte de 3 puntos, la media fue de 3,7 ± 1,6 puntos para excitación y lubricación, de 3,4 ± 1,5 puntos para el dominio de orgasmo y de 3,5 ± 1,7 para dolor. Por otra parte, para los dominios de deseo y satisfacción con un puntaje de corte de > 3,4 se observó una media de 3,4 ± 0,9 para dominios de deseo, y 3,7 ± 1,6 para el dominio de satisfacción. Conclusiones: Los resultados obtenidos están dentro de parámetros normales en cada dominio. Sin embargo, existe un pequeño porcentaje de encuestadas con puntajes menores a los mínimos; siendo fundamental generar en este grupo de mujeres mayores instancias y espacios de educación sexual, para la resolución de dudas y así tratar a ese porcentaje que hoy no disfruta de una función sexual placentera. Objective: Describe sexual function in university students belonging to universities in Chillán, Chile. Methods: Quantitative design, descriptive and cross-sectional study. The population of this study was comprised of 220 female university students with an age range of 17 to 40 years of age which fulfilled the criteria for eligibility. Information was collected through a Google survey due to government health mandates relating to COVID-19 in Chile. Sociodemographic variables were included, as well as surveys about the feminine orgasm and the Female Sexual Function Index. Results: According to the Female Sexual Function Index items, scores within normal ranges were observed in all domains, although a few of these scored closely to the cut-off points. On the domains of arousal, lubrication, orgasm and pain, with a cut-off score of 3 points, the average was 3.7±1.6 points arousal and lubrication, 3.4±1.5 points for the domain of orgasm and 3.5±1.7 for pain. On the other hand, for the domains of desire and satisfaction, with a cut-off score of >3.4, an average of 3.4±0.9 points was observed, and 3.7±1.6 for the domain of satisfaction. Conclusions: The results obtained are within normal parameters in each domain. However, a small percentage of surveyed women who scored below the minimum exists; it is fundamental to generate, for this group of women, better spaces and opportunities for sexual education in order to answer their questions and help them in their issues to better provide treatment for the women who are unable to fully enjoy sex