A c.3037G>A mutation in FBN1 gene causing Marfan syndrome with an atypically severe phenotype
Marfan syndrome is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, mostly caused by mutations in the FBN1 gene, which is located on chromosome 15q21.1 and encoding fibrillin 1. We report a case of Marfan syndrome presenting with severe ocular and systemic manifestations, such as cardiac congenital anomalies. The patient underwent a multidisciplinary approach and his clinical diagnosis was associated with a c.3037G>A mutation in the FBN1 gene. Identification of this genetic alteration should instigate a prompt multidisciplinary assessment and monitoring, in order to prevent devastating consequences such as cardiac and ocular phenotype. Molecular modeling of the mutation highlighted the importance of the preservation of the calcium-dependent structure of an epidermal- growth-factor-like domain of fibrillin-1 and consequently the microfibrillar formation process. This report aims to highlight the importance of an early clinical and molecular diagnosis and once more, the importance of the multidisciplinary approach of this genetic entity.
Prehipertension: influence of psychological stress in adolescents
The article examines the association between psychological stress (PS) and prehypertension (PH) in 690 adolescents, 260 males and 430 females, whose average age was 15.2 years (SD = 1.5). Their blood pressure (BP) was measured on separate days at school, by the oscillometric method (Dinamap) in a seating position. All of them completed a survey assessing life events and social readjustment (both scales associated with life stressors in adolescence). Participants were classified according to BP levels in prehypertensive (PH) and normotensive (N). The presence of PS was evaluated as severe stressful life events. The Chi-square test was used to study the association between PS and the presence of PH. The results showed the presence of PH in 9.2% (n = 24) in males and 3.5% (n = 15) in females, while the presence of PS ocurred in 70 males (26.9%) and 155 females (36.0%).When applied to the whole data, the Chi-square statistical test showed no association between PS and the condition of prehypertension [PH with PS = 15 vs. N with PS = 24, (P= 0.42)]. However, when subjects were classified by gender, there was a significant association between PS and PH in female adolescents [PH with PS = 9 vs N with PS = 6 (P = 0.04)]. This result suggests that, at early ages, female adolescents may be more vulnerable than males to PS as a determining factor to the condition of PH.
[Association of high sensitivity C-reactive protein with diet composition in Mexican school children]
The high-Sensitivity C-Reactive Protein (hs-CRP) is a cardiovascular risk marker. In healthy Mexican children, there islittle evidence that shows any relationship between serum levels of this marker with diet. The objective of this studywas to associate serum levels of hs-CRP with the diet composition in Mexican school children. The cross-sectional study included 300 seemingly healthy children of 10 to 12 years of age, 53.7% were girls and 46.3% boys.hs-CRP quantification was determined by nephelometry. The diet was quantified with a validated food frequency questionnaire. A descriptive statistical analysis, correlation and multivariate regression models were performed by using the SPSS v18 statistical software. The median of the hs-CRP was 0.3 mg / L (range: 0.3 to 6.8 mg / L). A significant direct correlation was found between serum hs-CRP with protein intake (rho=0.126, p=0.029), total fatty acids (rho = 0.128, p = 0.027) and saturated fatty acids (rho = 0.159, p = 0.006). hs-CRP was associated with the intake of protein (β = 0.203, p = 0.037) by multiple regression analysis, and inversely with whole grains (β = -0.175, p = 0,002). No significant association was found with the rest of the other variables. The serum concentration of hs-CRP was directly associated with the consumption of protein, total and saturated fatty acids and was indirectly proportional with the consumption of whole grains.
Inotropic and chronotropic effects of propranolol in isolated atrium of rats with fructose-induced insulin-resistance
Insulin resistance (IR) is a metabolic deficiency associated with type 2 diabetes and commonly related to the pathogenesis of cardiovascular diseases, being the determining factor of the metabolic syndrome. This research aims to understand the chronotropic and inotropic effects of Propranolol in isolated atrium of rats with fructose-induced insulin-resistance. For this reason, 16 male Sprague-Dawley rats were assigned to two groups and given ad libitum access to one of the following diets: Perrarina® dog chow or Perrarina® dog chow supplemented with vegetable shortening and with fructose (20%) and sucrose (20%) added to the water supply. Both groups were maintained on their respective dietary regimens for eight months. At the end of this period insulin resistance was verified by routine blood test. The rat hearts were rapidly removed, and the atria were dissected and kept in Krebs solutions (37ºC, pH 7.4; 95% O2 - 5% CO2) in an isolated organ bath Letica®, connected to a polygraph Grass®, registering atria frequency. The Student´s t-test was used to evaluate statistical differences between the two groups (p<0.05). Cumulative dose-response curves with isoproterenol were established in basal condition, and after fifteen minutes of pre-incubation with propranolol (1x10-6 M). A significant positive chronotropic effect was observed in IR rats (68.92±4.16 vs 44.92±4.08 beats/sec of control; p<0.001). The maximum force of atrial contraction after pre-incubation with propranolol was significantly higher in the IR group (91.67±2.10 vs 42.6 ± 3.5; p<0.001). These findings suggest that a blunted response of atrial β-adrenoceptor to propranolol exists in rats with fructose- induced insulin-resistance.
[Molecular epidemiology of KPC-producing Klebsiella pneumoniae isolated from patients in two public hospitals in Carabobo and Zulia states, Venezuela]
Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria (K. pneumonia carbapenemase) are the most important causative agents of nosocomial infections worldwide. These isolates have been identified in Venezuela, but little is known about their local spread. The aim of this study was to perform molecular epidemiology of KPC-producing K. pneumoniae isolated from two public hospitals in the Carabobo and Zulia states of Venezuela. Thirty-two K. pneumoniaei solates, phenotypically classified as KPC producers were subjected to PCR to detect the presence of blaKPC genes and their location within transposon Tn4401, and the blaKPC product was sequenced to identify the KPC allele. Genotypic analysis was performed using repeated extragenic palindromic PCR (rep-PCR) and Multi Locus Sequence Typing (MLST). Finally, a conjugation assay determined whether the blaKPC genes were carried on transferable plasmids. The results indicate that the 32 isolates contained the blaKPC-2 variant associated with isoform Tn4401b, and were distributed in nine sequence types (ST), one of which was new. Conjugation assays indicate that 87.5% of the isolates contain the gene blaKPC on mobilizable plasmids. In these hospitals, the blaKPC-2 gene is spreading through the plasmids carrying the transposon Tn4401b. The most common ST belongs to Clonal Complexes CC258 and CC147, which play an important role in the dispersion of resistance to carbapenems worldwide.
[Evidences about combination use of acetylsalicylic acid (aspirin) and clopidogrel in acute coronary syndrome]
Thromboembolic diseases remain one of the most important causes of morbidity and mortality worldwide. The pathophysiologic mechanism underlying the acute coronary syndromes is coronary thrombosis. That is why the basis of its treatment has focused on antiplatelet, fibrinolytic and anticoagulant drugs. In a significant number of individuals, additional measures must be used, such as, for example, the coronary percutaneous intervention (angioplasty and placement of the so-called intracoronary stents). Aspirin has been regarded as the drug of first choice in the prevention of thromboembolic diseases. The combination aspirin-clopidogrel has represented a highly efficient therapeutic measure for thromboembolic events. The introduction of fixed combination tablets represents a step forward in order to facilitate therapeutic compliance.
Cardio-Metabolic Health Venezuelan Study (EVESCAM): Design and Implementation
The EVESCAM (EstudioVenezolano de Salud Cardio-Metabólica) is the first national, population survey in Venezuela, designed to examine the prevalence of diabetes and cardio-metabolic risk factors and its relationship with lifestyle. It is a cross-sectional, cluster sampling study, which recruited 4454 participants aged ≥ 20 years. The data were collected in community health-care centers by trained health professionals and medical students. The data collected from each subject included, after informed consent, structured questionnaires (clinical, demographic, physical activity, nutritional and psychological), anthropometric measurements (weight, height and waist circumference), body fat by bioelectrical impedance, hand grip, blood pressure, electrocardiogram, and biochemical measurements (standard 75 g oral glucose tolerance test, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides). The data will be used to estimate the prevalence of overweight, obesity, prediabetes, diabetes, hypertension, dyslipidemias, sarcopenia and metabolic syndrome; and to examine their relationships with lifestyle factors. The risk of coronary heart disease and impaired glucose regulation will be estimated using the Framingham Coronary Heart Disease Risk Score and the Latin America adaptation of the Finnish Diabetes Risk Score (LA-FINDRISC), respectively. These results will guide national cardiovascular and diabetes prevention strategies, and will be available for government agencies to help in the implementation of public health policies.
High prevalence and poor control of hypertension in five venezuelan populations: the VEMSOLS study
The prevalence of hypertension in multiple regions of Venezuela is unknown. The objective of this study was to estimate the prevalence of hypertension in five populations from three regions. During 2006 to 2010, 1392 subjects aged 20 or older were selected by multistage stratified random sampling from all households in five municipalities from: Lara State (Western region), Merida State (Andean region), and Capital District (Capital region). Anthropometric measurements, blood pressure, and biochemical analysis were obtained from each participant. Mean age was 45.2 ± 0.4 years and 68% were females. The overall prevalence of hypertension was 31.3% (CI 95% 28.9 – 33.8), it was higher in men than women (38.1% [33.5 – 42.8] vs. 28.2% [25.4 – 31.2], respectively; p <0.001). The hypertensive participants were older, with higher body mass index (BMI), glucose, total cholesterol, LDL-c, and triglycerides; and lower values of HDL-c, than pre-hypertensive and normotensive participants (p < 0.05). In women, hypertension prevalence increased linearly for every decade of life and by category of BMI; whereas in men it increased until the fifth decade of life, and was similar in patients with overweight and obesity. The risk of hypertension increased with age, the presence of obesity, diabetes, overweight and family history of hypertension. Only 17.7% of the hypertensive subjects were both treated and controlled. In conclusion, about one third of the subjects evaluated had hypertension and about one fifth of them had their hypertension under control. In Venezuela, hypertension is a serious public health problem exacerbated by age and overweight.
[PAGOD syndrome and vascular anomalies: is a defect embryonic angiogenesis? A case report and review]
PAGOD Syndrome is an acronym for lung and pulmonary arteries hypoplasia, agonadism, omphalocele / diaphragmatic defect and dextrocardia. A series of 21 patients is described, where 90.5% had a 46,XY karyotype and only two cases 46,XX; 66.6% exhibited a female phenotype and 28.6% ambiguous genitalia. The occurrence of two patients 46,XX excludes the Y chromosome as a carrier of the genetic defect and raises the possibility of a recessive X-linked inheritance, without ruling out that the observed cases in siblings may be due to mutations in other genes as Stra6, VEGFA, VEGFB, VEGFC, and alternative splicing of transcripts VEGFA, HIF1, HIF2, among others. Congenital malformations were observed in patients’ genitals and gonads 85.7%, 66.6% in diaphragm and abdominal wall , heart 80.9%, 71.4% lungs, blood vessels 80.9% and 42.8% in abdomen. The review of patients has demonstrated a high degree of variability in the expression of malformations of organs and organ systems. Vascular malformations represent an important and characteristic component of PAGOD syndrome and whose base morphogenetic syndrome may be due to a defect in early embryonic angiogenesis with impact on organogenesis and system development. Among genes related to vascular remodeling during embryogenesis, tissue regeneration and carcinogenesis, the Endothelial Growth Factor D Vascular (VEGFD), located in the Xp22.31 region, with expression in lung, heart, small intestine, uterus, breast, neuroblastoma and neural tissue, represents a strong candidate for molecular analysis as a cause of the syndrome.
Detection of F8 mutations in carriers and patients with severe hemophilia A. Identification of a novel mutation
The molecular diagnosis of haemophilia A (HA) patients has many benefits including diagnosis confirmation and inhibitor risk development prediction. In female carries of a mutation, the molecular diagnosis allows for genetic counseling and prenatal diagnosis, which have become part of the comprehensive care for HA in many countries. Therefore, the aim of this study was to determine the F8 mutations in severe HA (sHA) patients and female carriers. In 12 patients with sHA, the presence of the intron 22 and intron 1 inversions was investigated using an inverse and a conventional PCR method, respectively. In patients negative for the inversions, the F8 gene was screened through conformation sensitive gel electrophoresis (CSGE) and further sequencing. The causative mutation was successfully identified in 6/12 patients, including the novel mutation p.G190C. The mothers of these six patients and those of seven other sHA patients molecularly diagnosed in a previous work were investigated for the presence of the genetic alterations found in their sons. All mothers were found to be carriers. This is the first study conducted in Venezuela which directly analyzes the F8 gene in potential carrier mothers to specifically identify the presence of the mutation that was detected in their sons, and complements a previous study on sHA patients. Our findings will facilitate the implementation of regular screening of HA carriers in our country and will allow a better care of bleeding symptoms and genetic counseling.
Psychotherapists: Should we meet Arthur Schopenhauer?
Arthur Schopenhauer (1788-1860) is known as the pessimist philosopher and the psychologist of the will. He anticipated some features of cognitive neuroscience, psychoanalysis and evolutionary psychology, but he is relatively unfamiliar to most contemporary mental health professionals. Schopenhauer conceived the will as the universe’s essence; purposeful human actions are a small part of it. We do not directly perceive the will, but only its phenomena through the ‘Veil of Maya’, which, in contemporary terms, refers to the cognitive and perceptual limits imposed by our own biological species. This is why Schopenhauer posits that we have a representation (idea) of the world. We have a direct access to the will by perceiving our body’s desires. The will is insatiable and selfish. Because of these will’s features, there is no possibility of collective or global salvation. However, individual or existential salvation may occur by denying the will through a path that includes: 1) an aesthetic experience particularly with the aid of art, that allows contemplation of the ´Platonic Ideas´, lessening desire and promoting knowledge through contemplation,; 2) the ethical experience refers to the insight about the unity of the universe, particularly by realizing the ubiquity of suffering and neediness, and 3) the metaphysical step which promotes compassion and asceticism. These philosophical principles may add to specific psychotherapeutic techniques in expanding the individual’s awareness beyond herself/himself, and thus arise and improve the psychological outcome.
Molecular identification of multidrug resistant Enterobacter hormaechei in Venezuela
Besides the importance of Enterobacter cloacae species complex as a nosocomial pathogen, little is known about the frequency of each species/genotype. Here, we describe a strain of E. hormaechei subsp. hormaechei isolated from a bronchial secretion of a patient, in the Intensive Care Unit at the General Hospital of Cumaná, Venezuela, who died due to complications of his infection. The molecular identification was done by sequencing the 16S rRNA gene and comparing it to sequences from the GenBank. This strain showed resistance to multiple families of antibiotics (MDR), and the genes blaKPC and blaVIM were detected by PCR. This is the first time E. hormaechei has been identified in Venezuela.
Neurotransmitter systems, neuroanatomical pathology and cell death in schizophrenia: update and perspectives
Schizophrenia is a thought disorder characterized by delusional thinking which may be accompanied by hallucinations involving any sensory modality. Schizophrenia may be associated with several neurologic and psychiatric disorders. Also, it may be induced by drugs. In spite of the similarity in psychoses symptomatology, it is unknown if it involves the same underlying neurobiologic mechanisms in those cases. Schizophrenic patients exhibit not only neuroanatomical alterations, but also, distortion of several neurotransmitter systems. Nowadays, the main theories in this regard involve dopaminergic hyperfunction and glutama- tergic hypofunction. Additionally, other systems involved in the schizophrenia pathophysiology are the nitric oxide pathway as well as GABAergic, glycinergic and serotonergic systems. Fur- thermore, those systems interact with each other to modulate nervous system development and cell survival. The alterations described in this paper may be part of a single cascade of events. Research in this field should focus on the elucidation of this chain to find its limits, the initial stage that originates it, and the final stage that has therapeutic implications.
Production of a conjugate between the rK346 antigen from Leishmania infantum and the horseradish peroxidase C for the detection of rK346 antibodies
It was designed and characterized a reporter system to be captured by an- tibodies bound to ELISA plates. The system was designed with the rK346 from Leishmania infantum, a highly antigenic and specific protein. The rK346 was coupled to the horseradish peroxidase C (HRPc) from Armoracia rusticana using glutaraldehyde or sulfo-SMCC. Gluta- raldehyde conjugation was performed in two steps. Separation of conjugates was carried out using a Sepharose S-200 in size exclusion chromatography (SEC); fractions were analyzed via HRPc activity and through ELISA plates sensitized with polyclonal anti-rK346 IgG puri- fied from rabbit serum. A heterogeneous population of conjugates rK346-HRPc was obtained with molecular weights ranging between 109.7 ± 16.5 to 67.6 ± 10.1 kDa; with rK346-HRPe stoichiometries of 1:2; 2:1; 3:1; and 2:2. Conjugation using sulfo-SMCC was carried out first by introducing -SH groups onto the HRPc using the SATA reagent and the antigen was modi- fied with sulfo-SMCC during 45 min. Separation and analysis of conjugates was performed similarly as with glutaraldehyde, resulting in a heterogeneous population of conjugates rK346- HRPc with molecular weights between 150.5 ± 22.6 to 80.0 ± 12.0 kDa; with rK346-HRPC stoichiometries of 2:1; 1:2; 2:2; and 1:3, with an increased conjugation efficiency in compari- son with glutaraldehyde. This enables sulfo-SMCC to be used as a potential reagent for cou- pling the antigen to the HRPc, to design an economic, specific and easy method to apply as a reporter system, available to assess individuals at risk and/or at early and late stages of visceral leishmaniasis.
Single nucleotide polymorphisms V4 and T1 of the ADAM33 gene in Venezuelan patients with asthma or chronic obstructive pulmonary disease
ADAM33 is a metalloproteinase important in the extracellular matrix for tissue remodeling, and, consequently, in asthma and chronic obstructive pulmonary disease (COPD). Several polymorphisms of the ADAM33 gene have been associated with enzyme activity. One of the most studied polymorphisms is V4, cytosine for guanine in the 3 'UTR region, and T1, adenine for guanine in the exon 19 of the gen. The aim of this study was to ascertain the possible association among single polymorphisms of ADAM33, V4 and T1, in Venezuelan patients with asthma or COPD. The polymorphisms V4 and T1 were analyzed in 303 individuals (103 asth- matic, 100 COPD and 100 controls) by PCR-RFLP (polymerase chain reaction and restriction fragment length polymorphisms). There was a significant difference (P<0.05) in the frequency of ADAM33 V4 polymorphism in both, asthmatic and COPD patients groups, as compared to controls. No significant differences (P=0.4) were found for T1 polymorphism. However, there were significant differences (P
Interleukin-6 and resistin in relation to anthropometric measurements in school children
The worldwide prevalence of childhood obesity has increased greatly over the past three decades. The increasing occurrence in children of disorders, such as type 2 diabetes, is believed to be a consequence of this obesity epidemic. Although the precise mechanisms are still unclear, dysregulated production or secretion of adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related me- tabolic diseases. The objective of the study was to determine the serum levels of interleukin-6 and resistin in relation to anthropometric measurements in school children. One hundred and three school-age children were studied. The anthropometric assessment included weight, hei- ght, triceps skinfold (TSF), waist circumference (WC), waist-to-height ratio (WiHtR) and Body Mass Index (BMI). Interleukin-6 and resistin levels were measured by ELISA. The data were analyzed using the SPSS version 20 statistical program and 95% CIs (p<0.05) was considelred significant. BMI values indicated that 15.54 % of the population was overweight, and 11.65 % was obese. We found that scholars with excess WC, WHtR and BMI (overweight) had higher levels of IL-6 and scholars with excess WC and WHtR had higher levels of resistin (p <0.05). Interleukin-6 showed positive correlation with WC (r=0.229; p = 0.020) and waist-to-height ratio (r=0.397; p
Cytokine and metalloproteinases in gingival fluid from patients with chronic periodontitis
The purpose of the present research was to determine the levels of IL- 1a, IL- 1 P, TNF-a, IL-6, IL-6sR, IL-8, IL-10, MMP-3 and EMP-8 in gingival crevicular fluid (GCF) of subjects with chronic periodontitis. Clinical measurements were carried out in 20 patients with chronic periodontitis and 11 periodontally healthy controls. The clinical indexes evalua- ted were: gingival index (GI), plaque index (PI), bleeding on probing (BOP), probing depth (PD) and clinical attachment loss (CAL); the measurements were taken at six sites per tooth in all teeth in each subject. GCF samples were taken from one tooth per quadrant, and the levels of mediators were measured using an ELISA test. Statistically significant differences were observed between patients and control group in relation to all clinical parameters evaluated (p<0.05). The gingival concentrations, in pg/mL, of IL-la (patients: 239.06 ± 65.5 vs control: 97.79 ± 15.81), IL-10 (patients: 157.19 ± 36.4 vs control: 63.44 ± 19.04), TNF-a (patients: 10.87 ± 1.7 vs control: 1.15 ± 0.84), IL-6 (patients: 3.77 ± 1.7 vs control: 0.43 ± 0.22), IL-6Sr (patients: 655.59 ± 185.8 vs control: 73.59 ± 23.18), IL-8 (patients: 496.3 ± 155.3 vs control: 206.13 ± 46.63), IL-10 (patients: 10.75 ± 3.6 vs control: 2.41 ± 0.57), MMP-3 (patients: 3531 ± 1558.2 vs control: 724.84 ± 289.51) and MMiP-8 (patients: 8231.70 ± 1279.2 vs control: 1534.67± 814.90) were significantly greater in patients with periodontal disease than in the control group (p<0.00 1). The higher levels of the cytokines and metalloproteinases obtained in this study were significantly associated with the severity of the periodontal disease.
Significant associations between C-reactive protein levels, body adiposity distribution and peripheral blood cells in school-age children
Obesity is associated with a state of chronic low-grade inflammation. Ge- nerally, there are significant correlations between body mass index and increased C-reactive protein levels. We investigated the relationship of high sensitivity C-reactive protein (hsCRP) levels with body adiposity distribution and blood cell count in obese children. A cross-sec- tional study was performed in 225 Mexican children. In the study were included 106 obese and 119 normal-weight children, aged 6-13 years old. The body composition was evaluated by BMI, body circumferences and skinfold thickness. hsCRP levels and hematological para- meters were analyzed in all children. The hsCRP levels were higher in obese children than in the control group (1.5 and 0.41 mg/L respectively, P<0.001). Interestingly, hsCRP levels >3 mg/L were associated with the increase of circumferences of the waist, hip and arms (ORs= 9.08, 6.78 and 8.73, respectively, P<0.001), and,a higher thickness of triceps, subscapular and suprailiac skinfolds (ORs= 4.73, 6.39 and 5.26, respectively, P=0.001), as well as a higher leukocyte and platelet counts. The data suggest that hsCRP levels are associated with skinfold thickness and body circumferences, and a moderate relationship was found with leukocyte and Dlatelet counts in the studied children.
Subclassification of the molecular types of breast cancer based on the expression of immunohistochemical markers and evolution
Breast carcinomas have been classified from the molecular point of view into four major groups (Luminal A, Luminal B, HER2 and triple negative). However, these groups are not homogeneous and there is a need to establish subcategories that can be identified by immunohistochemistry (IHC), to better predict prognosis and carry out treatments that are more effective. This study was conducted in 354 patients diagnosed with invasive ductal breast carci- noma. The expression of 22 molecules was analyzed by tissue matrices and the results obtained were compared with molecular classes defined by IHC, according to the expression of estrogen receptor (ER), progesterone receptor (PR) and HER2, and the overall survival. The Luminal A molecular class can set various prognosticosubgroups: the subgroup with exclusive expression of ER and PR, with Ki-67 ≤14%, with a better prognosis, and the subgroup of Luminal A with Ki-67> 14% or other expression related to the basal phenotype markers. Luminal B group can be divided into subtypes according to the expression of Ki-67 (cutoff at 25%). In the HER2 class it seems important the Ki-67 index for forecasting (cutoff at 25%). The TN class can be divided according to the rate of proliferation into two prognostic categories, with a better prog- nosis for tumors with Ki-67 index ≤25%.
Editorial Considerations on the "Manifesto for a Post-Mate-rialist Science"