Catalytic and binding sites prediction in globular proteins through discrete Markov chains and network centrality measures.

In this work we use a discrete Markov chain approach combined with network centrality measures to identify and predict the location of active sites in globular proteins. To accomplish this, we use a three-dimensional network of proteinCαatoms as nodes connected through weighted edges which represent the varying interaction degree between protein's atoms. We compute the mean first passage time matrixH= {Hji} for this Markov chain and evaluate the averaged number of steps ⟨Hj⟩ to reach single nodenjin order to identify such residues that, on the average, are at the least distant from every other node. We also carry out a graph theory analysis to evaluate closeness centralityCc, betweenness centralityCband eigenvector centralityCemeasures which provide relevant information about the connectivity structure and topology of theCαprotein networks. Finally we also performed an analysis of equivalent random and regular networks of the same sizeNin terms of the average path lengthLand the average clustering coefficient⟨C⟩comparing these with the corresponding values forCαprotein networks. Our results show that the mean-first passage time matrixHand its related quantity ⟨Hj⟩ together withCc,CbandCecan not only predict with relative high accuracy the location of active sites in globular proteins but also exhibit a high feasibility to use them to predict the existence of new regions in protein's structure to identify new potential binding or catalytic activity or, in some cases, the presence of new allosteric pathways.

Cacalol Acetate, a Sesquiterpene from Psacalium decompositum, Exerts an Anti-inflammatory Effect through LPS/NF-KB Signaling in Raw 264.7 Macrophages.

Inflammatory diseases remain critical health problems worldwide. The search for anti-inflammatory drugs is a primary activity in the pharmaceutical industry. Cacalol is a sesquiterpene with anti-inflammatory potential that is isolated from Psacalium decompositum, a medicinal plant with several scientific reports supporting its anti-inflammatory activity. Cacalol acetate (CA) is the most stable form. Nevertheless, the participation of CA in the main signaling pathway associated with inflammation is unknown. Our aim was to study the anti-inflammatory effect of CA and to determine its participation in NF-κB signaling. In TPA-induced edema in mice, CA produced 70.3% inhibition. To elucidate the influence of CA on the NF-κB pathway, RAW 264.7 macrophages were pretreated with CA and then stimulated with LPS, evaluating NF-ΚB activation, IKK phosphorylation, IΚB-α, p65, cytokine expression, and COX-2 release and activity. CA inhibited NF-κB activation and its upstream signaling, decreasing phosphorylation IKB-α and p65 levels. CA also reduced expression and secretion of TNF-α, IL-1ß, and IL-6. Additionally, it decreased the activity and expression of COX-2 mRNA. These data support that CA regulates the NF-κB signaling pathway, which might explain, at least in part, its anti-inflammatory effect. CA is a bioactive molecule useful for the development of anti-inflammatory agents with innovative mechanisms of action.

Effect of Moringa oleifera consumption on diabetic rats.

BACKGROUND: Therapeutic use of leaves of M. oleifera has been evaluated in diabetes because of its possible capacity to decrease blood glucose and lipids concentration after ingestion, as result of the polyphenols content and others compounds. Nevertheless most results have been obtain from leaf extract, therefore this study would use leaf powder as the regular way of consumption of population to know effects over toxicity glucose, triglycerides, cholesterol, corporal weight, and predominant groups of microbiota. METHODS: Powdered leaf was administrated in different doses to know toxicity and genotoxicity using LD50 and micronuclei assay. Hyperglycemia was induced by alloxan on Sprague Dawley rats. Glucose and body weight were measured once a week meanwhile cholesterol and triglycerides were analyzed at the end of the study by commercial kits. Different organs were examined by hematoxylin-eosin technique. Lactic acid bacteria and Enterobacteriaceae were enumerated from stool samples. RESULTS: The tested doses revealed no lethal dose and no significant differences in genotoxicity parameter. The consumption of the leaves showed a hypoglycemic effect (< 250 mg/dL in diabetic M. oleifera treated group), however in corporal weight showed an increased (> 30 g over no M. oleifera treated groups). There was no change in enumeration of lactic acid bacteria (8.4 CFU/g) but there were differences in the predominance of type of lactobacillus and enterobacteria enumeration. CONCLUSIONS: These results help to increase information over the most popular use of M. oleifera and its safety. However there are needed more studies over the hypoglycemic mechanisms and effects over intestinal microbiota.

Role of single-point mutations and deletions on transition temperatures in ideal proteinogenic heteropolymer chains in the gas phase.

A coarse-grained statistical mechanics-based model for ideal heteropolymer proteinogenic chains of non-interacting residues is presented in terms of the size K of the chain and the set of helical propensities [Formula: see text] associated with each residue j along the chain. For this model, we provide an algorithm to compute the degeneracy tensor [Formula: see text] associated with energy level [Formula: see text] where [Formula: see text] is the number of residues with a native contact in a given conformation. From these results, we calculate the equilibrium partition function [Formula: see text] and characteristic temperature [Formula: see text] at which a transition from a low to a high entropy states is observed. The formalism is applied to analyze the effect on characteristic temperatures [Formula: see text] of single-point mutations and deletions of specific amino acids [Formula: see text] along the chain. Two probe systems are considered. First, we address the case of a random heteropolymer of size K and given helical propensities [Formula: see text] on a conformational phase space. Second, we focus our attention to a particular set of neuropentapeptides, [Met-5] and [Leu-5] enkephalins whose thermodynamic stability is a key feature on their coupling to [Formula: see text] and [Formula: see text] receptors and the triggering of biochemical responses.

Reactive oxygen species production, induced by atmospheric modification, alter conidial quality of Beauveria bassiana.

AIM: The aim of this study was to determine the relationship between reactive oxygen species (ROS) production and conidial infectivity in Beauveria bassiana. METHODS AND RESULTS: Beauveria bassiana Bb 882.5 was cultured in solid-state culture (SSC) using rice under three oxygen conditions (21%, or pulses at 16 and 26%). Hydrophobicity was determined using exclusion phase assay. Bioassays with larvae or adults of Tenebrio molitor allowed the measurements of infectivity parameters. A fluorometric method was used for ROS quantification (superoxide and total peroxides). NADPH oxidase (NOX) activity was determined by specific inhibition. Conidial hydrophobicity decreased by O2 pulses. Mortality of larvae was only achieved with conidia harvested from cultures under 21% O2 ; whereas for adult insects, the infectivity parameters deteriorated in conidia obtained after pulses at 16 and 26% O2 . At day 7, ROS production increased after 16 and 26% O2 treatments. NOX activity induced ROS production at early stages of the culture. CONCLUSION: Modification of atmospheric oxygen increases ROS production, reducing conidial quality and infectivity. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study in which conidial infectivity and ROS production in B. bassiana has been related, enhancing the knowledge of the effect of O2 pulses in B. bassiana.

How well can levator ani muscle morphology on 3D pelvic floor ultrasound predict the levator ani muscle function?

INTRODUCTION AND HYPOTHESIS: The aim of our study was to assess the performance of levator ani muscle deficiency (LAD) evaluated by 3D endovaginal ultrasound (EVUS) to detect pelvic floor muscle function as assessed by digital examination. METHODS: This cross-sectional study was conducted among 77 patients referred to our urogynecology clinic for pelvic floor dysfunction symptoms. Patients underwent physical examinations including digital pelvic muscle strength assessment using the Modified Oxford scale (MOS). EVUS volumes were evaluated and levator ani muscles were scored according to a validated LAD scoring system. MOS scores were categorized as nonfunctional (scores 0-1) and functional (scores 2-5). RESULTS: Mean age of participants was 56 (SD ± 12.5) and 71% were menopausal. Overall, 32.5% had nonfunctional muscle strength and 44.2% were classified as having significant LAD. LAD identified by ultrasound had a sensitivity of 60% (95% CI 41 -79%) for detecting nonfunctional muscle and a specificity of 63% (95% CI 50 -77%) for detecting functional muscle. Overall, LAD demonstrated fair ability to discriminate between patients with and those without poor muscle function (area under the ROC curve = 0.70 [95% CI 0.58-0.83]). Among patients with an LAD score of 16-18, representing almost total muscle avulsion, 70% had nonfunctional MOS scores, whereas in patients with normal/minimal LAD (scores of 0-4), 89.5% had functional MOS scores. CONCLUSIONS: Levator ani deficiency and MOS scales were moderately negatively correlated. Among patients with normal morphology or the most severe muscle deficiency, LAD scores can identify the majority of patients with functional or nonfunctional MOS scores respectively.

Sonographic predictors of obstructive defecatory dysfunction.

INTRODUCTION AND HYPOTHESIS: We aimed to evaluate the association between obstructive defecatory symptoms in women with levator ani deficiency (LAD), worsened minimum levator hiatus measurements, widened anorectal angle (ARA), and increased levator-plate descent angle (LPDA). METHODS: Using a cross-sectional study design, patients who had undergone 3D endovaginal ultrasound (3D EVUS) imaging of the pelvic floor were sampled and categorized into two groups: those with and those without obstructive defecatory symptoms (ODS) based on their Colorectal and Anal Distress Index (CRADI-8) questionnaire. The levator ani (LA) muscle was scored based on severity of defect. ARA and LPDA were measured and dichotomized (ARA ± 170°; LPDA ± 9°. RESULTS: One hundred patients were analyzed: 52 asymptomatic and 48 with ODS. The mean (standard deviation ) age was 59 years (SD ±14.97). There was no difference in the distribution of LAD severity between groups (p = 0.1438) or mean minimal levator hiatus (MLH) (p = 0.3326). ARA and LPDA were significantly different in those with ODS compared with their asymptomatic counterparts (p < 0.0001 and 0.0004, respectively) (Table 1). On multivariable logistic regression, ARA and LPDA were included in the final model. Patients with an ARA >170° had seven times the odds of ODS than those with ARA ≤170° [odds ratio (OR) = 7.01, 95 % confidence interval (CI) 2.30-21.35; p = 0.0006). Patients with an LPDA <9° had 3 times the odds of ODS than those with an LPDA ≥9° (OR = 3.30, 95 % CI 1.22, 8.96, p = 0.0190). CONCLUSIONS: This study demonstrates that increased levator plate descent and widened ARA as measured on 3D endovaginal ultrasound imaging are associated with ODS.

Is there a correlation between levator ani and urethral sphincter complex status on 3D ultrasonography?

INTRODUCTION AND HYPOTHESIS: To determine the correlation between levator ani deficiency (LAD) and urethral sphincter complex measurements as visualized on 3D endovaginal ultrasonography, and to compare the LAD score with continence status. METHODS: This was a retrospective analysis of patients seen at our institution between January 2011 and August 2013. Patients were dichotomized into those with urodynamic stress urinary incontinence (SUI) and those with no SUI. Levator ani status was evaluated using a validated scoring system yielding scores of 0 - 6 (normal levator ani/mild LAD), 7 - 12 (moderate LAD), and 13 - 18 (severe LAD). The length, horizontal diameter, and cross-sectional area of the urethra, and the length, width, and the area of the rhabdomyosphincter and smooth muscle sphincter were likewise measured using 3D ultrasound volumes. RESULTS: Of the 80 patients included, 54 (67.5%) had SUI and 26 (32.5%) were continent. 18 (22.5%) had evidence of mild LAD, 54 (67.5%) had moderate LAD, and 8 (10.0%) had severe LAD. Among patients with SUI, those with normal levator ani muscles or mild LAD had greater urethral smooth muscle width than those with moderate and severe LAD (p = 0.0238). A greater proportion of patients with SUI also had moderate to severe LAD than continent patients (p = 0.0177, OR 3.59, 95% CI 1.21 - 10.65). There was no difference in LAD distribution by type of stress incontinence (presence or absence of intrinsic sphincter deficiency; p = .2377). CONCLUSIONS: LAD and urethral sphincter complex status, as visualized on 3D ultrasonography, are independent factors. Moderate to severe LAD is more prevalent in patients with SUI.

An ultrasound approach to the posterior compartment and anorectal dysfunction.

INTRODUCTION AND HYPOTHESIS: Patients with anorectal dysfunction are common and can be quite challenging to diagnose. The common underlying causes for such conditions are usually anatomical in nature, which may be difficult to fully evaluate by clinical examination alone. The aim of this video was to demonstrate how multicompartmental ultrasound imaging can be utilized clinically in the evaluation of patients with anorectal dysfunction. METHODS: Pertinent ultrasound findings of the common anatomical causes of defecatory dysfunction were discussed in this video. RESULTS: Different ultrasound techniques were shown. CONCLUSION: In conclusion, multicompartmental ultrasound imaging is an easy, cost-efficient, and valuable tool in the evaluation of patients with anorectal dysfunction.

Incremental Value of Live/Real Time Three-Dimensional over Two-Dimensional Transesophageal Echocardiography in the Assessment of Atrial Septal Pouch.

An atrial septal pouch (ASP) results from partial fusion of the septum primum and the septum secundum, and depending on the site of fusion, the pouch can be left-sided (LASP) or right-sided (RASP). LASPs have been described in association with thrombi found in patients admitted with acute strokes, raising awareness of its potential cardioembolic role, especially in those with no other clearly identifiable embolic source. We retrospectively studied 39 patients in whom the presence of an ASP had been identified by three-dimensional transesophageal echocardiography (3DTEE) and who had a two-dimensional transesophageal echocardiogram (2DTEE) performed during the same clinical encounter. The incremental value provided by 3DTEE over 2DTEE included the detection of six ASPs not found by 2DTEE; the detection of two ASPs in the same subject (in four patients) not identified by 2DTEE; larger ASP measurements of length and height in over 80% of the cases; and measurement of the ASP width (elevational axis) for the calculation of the area of the ASP opening, because of its unique capability to view the pouch en face. In addition, the volume of ASP and of the echogenic masses contained in the ASP (four of 39 patients) could be calculated by 3DTEE, which is a superior parameter of size characterization when compared to individual dimensions. One of these patients who presented with ischemic stroke diagnosed by magnetic resonance imaging had a large (>2 cm) mass in a LASP, with echolucencies similar to those seen in thrombi and associated with clot lysis and resolution. This mass completely disappeared on anticoagulant therapy lending credence that it was most likely a thrombus. There was no history of stroke or any other type of embolic event in the other three patients with masses in ASP. In conclusion, this retrospective study highlights the incremental value of 3DTEE over 2DTEE in the comprehensive assessment and characterization of ASPs, which can aid in the clarification of their role in cryptogenic stroke patients.

3D pelvic floor ultrasound findings and severity of anal incontinence.

INTRODUCTION AND HYPOTHESIS: The aim of our study was to determine the association between the severity of anal incontinence and levator ani deficiency, anal sphincter defects, anorectal angle, and colonic motility abnormalities. METHODS: This was a retrospective study. Subjects were categorized into three groups: normal, minor anal incontinence, and major anal incontinence according to their answers to the PFDI-20 questionnaire. 3D endovaginal ultrasound was utilized to assess levator ani muscle and the anorectal angle. Levator ani muscle subdivisions were scored based on avulsion from the pubic bone and muscle thickness, based on our previous work. 3D endoanal ultrasound was utilized to assess anal sphincters. Colonic motility abnormalities were defined as diarrhea, constipation or both. RESULTS: Ninety-seven patients were included in the analysis: 45 with major anal incontinence, 29 with minor anal incontinence, and 23 continent women. On multivariate logistic regression, sphincter defect, anorectal angle, and colonic motility abnormalities were associated with anal incontinence severity. Women with an external anal sphincter defect had a 20.36-fold chance of having severe anal incontinence compared with patients with no defect (OR 20.36, 95% CI 5.4, 76.6); those with both defective sphincters had a 102.5-fold chance of having severe anal incontinence (OR 102.5, 95% CI 10.2, >999). Anorectal angle ≥170° was significantly associated with the severity of anal incontinence (OR = 4.07, 95% CI 1.53, 10.79), as was the presence of colonic mobility abnormality (OR 5.31, 95% CI 1.86, 15.19). CONCLUSIONS: 3D pelvic floor ultrasound can be an efficient tool for anal incontinence evaluation in women. Anal sphincter defects, colonic motility abnormalities, and anorectal angle were associated with the severity of anal incontinence. While there was a trend toward worsening levator ani deficiency among those with major anal incontinence, this did not reach statistical significance.

Interrater reliability of assessing levator ani deficiency with 360° 3D endovaginal ultrasound.

INTRODUCTION AND HYPOTHESIS: Three-dimensional endovaginal ultrasound has been used for evaluation of levator ani muscle deficiency. The aim of this study was to assess interrater agreement/reliability of 3D endovaginal ultrasound for scoring levator ani deficiency (LAD). METHODS: This was a cross-sectional study. Women referred to our urogynecology clinic for different pelvic floor dysfunction symptoms during November 2010-November 2012 were recruited. All patients underwent physical examination, including Pelvic Organ Prolapse Quantification (POP-Q) examination and high-resolution 3D endovaginal ultrasound. The levator muscle was divided into three subgroups based on our prior work: the puboperinealis/puboanalis (PA), puborectalis (PR), and iliococcygeus/pubococcygeus (PV). Subgroups were evaluated in their specific axial plane and were scored according to thickness and detachment from the pubic bone. Scoring was conducted by four raters blinded to case status and to one another's scores. RESULTS: Ninety patients were recruited. The median age was 52 (range 24-86). Median body mass index (BMI) was 28.08 (range 17.08-51.39). Fifty percent of patients were menopausal. The range of exact agreement for total LAD score was 77-90 %. All the correlation coefficients at the individual sites as well as the overall scores were positive at above 0.63 and significant at <0.0001 level. CONCLUSIONS: Our study demonstrates excellent agreement between raters assessing levator ani muscle deficiency using 3D endovaginal ultrasound. This level of concordance supports the reliability of the 3D endovaginal ultrasound technique and scoring method among raters [corrected].

Early effect of essential hypertension on the left ventricular twist-displacement loop by two-dimensional ultrasound speckle tracking imaging.

OBJECTIVE: To investigate two-dimensional (2D) ultrasound speckle tracking imaging (STI) in the evaluation of the early changes in the left ventricular (LV) twist-displacement loop in patients with hypertension (EH). METHODS: Sixty-five EH patients with left ventricular normal geometry (LVN) - including 33 cases with non-left atrial enlargement (NLAE) and 32 cases with left atrial enlargement (LAE) - along with 45 healthy individuals were enrolled in this study. Basal and apical 2D LV short-axis images were acquired and analyzed to obtain the LV rotation (LVrot) and LV radial displacement. Once the LV twist and LV radial displacement were calculated, an LV twist-displacement loop was constructed. Group comparisons between peak twist (Ptw), twist at mitral valve opening (MVOtw), untwisting rate (Utw R), systolic radial displacement (SD), systolic slope (SS), isovolumic relaxation radial displacement (IVRD) and isovolumic relaxation slope (IVRS) were performed. RESULTS: (1) The Ptw and MVOTw were greater in the NLAE and LAE groups when compared to the normal group while the UTw R was lower in likewise comparison. (2) The LV twist was correlated to the radial displacement in systole and in the isovolumic relaxation period. The SS and IVRS were greater in the NLAE and LAE groups when compared to the normal group. CONCLUSIONS: The LV twist-displacement loop can be reconstructed noninvasively by 2D ultrasound STI. EH affects the systolic and early diastolic component of the twist-displacement loop by increasing the LV twist and decreasing the LV untwisting respectively impairing LV relaxation. The assessment of the LV twist-displacement loop may be useful in the evaluation of early features of LV dysfunction in EH patients.

[Executive functions in patients with obstructive sleep apnea: exploring the prefrontal model]. / Funciones ejecutivas en pacientes con apnea obstructiva del sueño: explorando el modelo prefrontal.

INTRODUCTION: According to the prefrontal model, individuals with obstructive sleep apnea (OSA) manifest behaviours mimicking dysexecutive syndrome as a result of blood gas abnormalities and sleep fragmentation. OBJECTIVE: To compare executive functions in OSA patients with normative values and explore their relationship with blood gas abnormalities and sleep fragmentation. PATIENTS AND METHODS: Patients were recruited from the wider community and from a tertiary care hospital. The score obtained in the neuropsychological assessment was compared with Student's t-test for a sample. A multiple linear regression analysis was subsequently estimated, using polysomnographic parameters of hypercapnia, hypoxemia and sleep fragmentation as the predictor variables, and the executive function score as the variable to be predicted. RESULTS: Although the neuropsychological assessment performance of 26% of this sample was classified as executive impairment, indicators of sleep fragmentation and gas abnormalities failed to predict the performance of executive functions. CONCLUSION: A proportion of the patients with OSA presented performance similar to a dysexecutive syndrome; however, the factors underlying and fostering this type of cognitive manifestation remain unclear. Early treatment for this public health problem could be the best tool available for improving quality of life and preventing health risks.

TITLE: Funciones ejecutivas en pacientes con apnea obstructiva del sueño: explorando el modelo prefrontal.Introducción. El modelo prefrontal propone que los individuos con apnea obstructiva del sueño (AOS) manifiestan conductas similares a un síndrome disejecutivo como resultado de las alteraciones de gases en la sangre y la fragmentación del sueño. Objetivo. Comparar las funciones ejecutivas en pacientes con AOS con valores normativos y explorar su relación con las alteraciones de gases en la sangre y la fragmentación del sueño. Pacientes y métodos. Se reclutó a pacientes de la comunidad general y de un hospital de tercer nivel. La puntuación obtenida en la evaluación neuropsicológica se contrastó con la t de Student para una muestra. Posteriormente, se estimó un análisis de regresión lineal múltiple mediante parámetros polisomnográficos de hipercapnia, hipoxemia y fragmentación del sueño como variables predictoras, y la puntuación de funciones ejecutivas como variable que se debe predecir. Resultados. Pese a que el desempeño en la evaluación neuropsicológica del 26% de esta muestra se clasificó como alteración ejecutiva, los indicadores de fragmentación del sueño y alteraciones de gases no predijeron el desempeño ejecutivo. Conclusión. Una fracción de los pacientes con AOS mostró un desempeño similar a un síndrome disejecutivo; no obstante, permanecen indefinidos los factores que subyacen y favorecen este tipo de manifestaciones cognitivas. La atención temprana de este problema de salud pública podría ser la mejor herramienta disponible en aras de mejorar la calidad de vida y prevenir riesgos a la salud.

The determinants of minimal levator hiatus and their relationship to the puborectalis muscle and the levator plate.

OBJECTIVE: To determine the muscles comprising the minimal levator hiatus. DESIGN: Cross-sectional study. SETTING: The University of Oklahoma Health Sciences Center, USA. POPULATION: Eight female fresh frozen pelves and 80 nulliparouswomen. METHODS: Three-dimensional endovaginal ultrasound was performed in eight fresh frozen female pelves. The structures of the levator hiatus were tagged with needles and the cadavers were dissected to identify the tagged structures. A group of 80 nullipara underwent 3D endovaginal ultrasound, and the minimal levator hiatus area, puborectalis area, and anorectal angle were assessed, and normal values were obtained. MAIN OUTCOME MEASURES: Anatomic borders of minimal levator hiatus and normality in pelvic floor measurements. RESULTS: The pubococcygeus forms the inner lateral border and anterior attachment of the minimal levator hiatus to the pubic bone. The puboanalis fibres are immediately lateral to pubococcygeus attachments. There are variable contributions of the puborectalis fibres lateral to the puboanalis attachment. The posterior border of the minimal levator hiatus is formed by the levator plate. Eighty community-dwelling nulliparous women underwent 3D endovaginal ultrasound. The median age was 47 years (range 22-70 years). The mean of minimal levator hiatus and puborectalis hiatus areas were 13.4 cm(2) (±1.89 cm(2) SD) and 14.8 cm(2) (±2.16 cm(2) SD). The mean anorectal and levator plate descent angles were 156° (±10.04° SD) and 15.9° (±8.28° SD). CONCLUSION: Anterior and lateral borders of the minimal levator hiatus are formed mostly by pubococcygeus. The puborectalis, pubococcygeus, and iliococcygeus form the bulk of the levator plate.

Visualization of periurethral structures by 3D endovaginal ultrasonography in midsagittal plane is not associated with stress urinary incontinence status.

INTRODUCTION AND HYPOTHESIS: Our aim was to determine the association between visualizing periurethral structures in the midsagittal plane with 3D endovaginal ultrasonography (EVUS) and stress urinary incontinence (SUI) status. METHODS: In a cross-sectional study, we measured urethral length and scored for presence or absence of the following in midsagittal plane in patients with and without stress SUI: striated urogenital sphincter, longitudinal/circular smooth muscle, vesical trigone, trigonal plate, trigonal ring, and compressor urethra. Summary statistics were calculated for the study population. Fisher's exact test was used to compare continuous data. Categorical data was compared with the chi-square. RESULTS: Data from 161 patients was available for review. Mean patient age was 54.4 [±15.6 standard deviation (SD)] years, and median parity was two (range 0-5). Among these women, 137/161(85%) did not have SUI and 24/(15%) did; 20/161 (12%) had anterior-compartment prolapse stage 2 or greater, and among them, only two had urinary incontinence (UI). No association was found between UI and visualization of the periurethral structures. Mean urethral lengths did not differ between groups (p = 0.37). CONCLUSIONS: Visualization of periurethral structures by 3D EVUS in the midsagittal plane is not associated with SUI status.

UPD(14)mat and UPD(14)mat in concomitance with mosaic small supernumerary marker chromosome 14 in two new patients with Temple syndrome.

Temple syndrome (TS14) can be originated by maternal uniparental disomy (UPD(14)mat), paternal deletion, or epimutation, leading to disturbances in 14q32.2 imprinted region. The most frequent phenotypic manifestations are prenatal and postnatal growth failure, hypotonia, developmental delay, small hands/feet, precocious puberty, and truncal obesity. However, the diagnosis can be challenging due to the clinical overlap with other imprinting disorders such as Silver-Russell or Prader-Willi syndromes. Although rare, TS14 has been also reported in patients with concomitant UPD(14)mat and mosaic trisomy 14. In the present report, the clinical and genetic profiles of two new patients with TS14 are described. SNParray and MS-MLPA, allowed the determination of segmental UPD(14)mat and the hypomethylation of MEG3 gene. Additionally, in one of our patients we also observed by cytogenetics a small supernumerary marker chromosome that led to partial trisomy 14 in mosaic. Only few patients with concomitant UPD(14)mat and mosaic partial trisomy 14 have been reported. Our patients share cardinal TS14 phenotypic features that are associated to the genetic abnormalities detected; however, we also observed some clinical features such as fatty liver disease that had not previously been reported as part of this syndrome. The detailed clinical, cytogenetical and molecular description of these two new patients, contributes to a more accurately delineation of this syndrome.

Translocation of non-interacting heteropolymer protein chains in terms of single helical propensity and size.

In this work we present an analytical framework to calculate the average translocation time τ required for an ideal proteinogenic polypeptide chain to cross over a small pore on a membrane. Translocation is considered to proceed as a chain of non-interacting amino acid residues of sequence {Xj} diffuses through the pore against an energy barrier Δℱ, set by chain entropy and unfolding-folding energetics. We analyze the effect of sequence heterogeneity on the dynamics of translocation by means of helical propensity of amino acid residues. In our calculations we use sequences of fifteen well-known proteins that are translocated which span two orders of magnitude in size according to the number of residues N. Results show non-symmetric free energy barriers as a consequence of sequence heterogeneity, such asymmetry in energy may be useful in differentiated directions of translocation. For the fifteen polypeptide chains considered we found conditions when sequence heterogeneity has not a significant effect on the time scale of translocation leading to a scaling law τ ∝ Nν, where ν ∼ 1.6 is an exponent that holds for most ground state energies. We also identify conditions when sequence heterogeneity has a great impact on the time scale of translocation, in consequence, no more scaling laws for τ there exist.

Origin of the myotonic dystrophy type 1 mutation in Mexican population and influence of Amerindian ancestry on CTG repeat allelic distribution.

Myotonic dystrophy type 1 is caused by expansion of a CTG trinucleotide repeat situated in the DMPK gene. Worldwide genetic studies suggest a single or limited number of mutational events cause the disease. However, distribution of CTG alleles and disease incidence varies among ethnicities. Due to the great ethnic diversity of the Mexican population, the present study was aimed at analyzing the impact of different lineages in shaping the CTG-repeat allelic distribution in the contemporary Mexican-Mestizo population as well as to shed light on the DM1 ancestral origin. Distribution of CTG-repeat alleles was similar among Mestizo and Amerindian subpopulations with (CTG)11-13 being the most frequent alleles in both groups, which implies that Mexican-Mestizo allelic distribution has been modeled by Amerindian ancestry. We diagnosed a relatively high number of cases, consistent with the high frequency of large-normal alleles found in Mexican subpopulations. Haplotype analysis using various polymorphic-markers in proximity to DMPK gene indicates that a single founder mutation originates myotonic dystrophy type 1 in Mexico; however, Y-STR haplogroups data and the presence of pre-mutated and large normal alleles in Amerindians support the hypothesis that both European and Amerindian ancestral chromosomes might have introduced the disease to the Mexican population, which was further disseminated through mestizaje.

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin.

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effect of DNA alkylating agents on BRCA1­ and BRCA2-deficient cell lines. The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide (NAM) on breast cancer cells with different BRCA1 expression or function, such as BRCA1­deficient MDA-MB-436 cells, low expression BRCA1 MCF-7 cells, and the BRCA1 wild­type MDA-MB-231 cells, to demonstrate its effects as a chemo­ or radiosensitizing agent. PARP activity was analyzed in MDA-MB-436, MCF-7 and MDA-MB-231 breast cancer cells subjected or not to NAM. Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence. Crystal violet assays were used to test growth inhibition and the chemo­ and radiosensitization effects of NAM were investigated using clonogenic assays. Significant differences among data sets were determined using two-tailed ANOVA and Bonferroni tests. We demonstrated that NAM reduces PARP activity in vitro, and in cells subjected or not to DNA damage, it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA-MB-436 and MCF-7 cells. Downregulation of PARP1 with siRNA led to modest growth inhibition, which was further increased by cisplatin. Nicotinamide also induced radiosensitization in MDA-MB-436 and MDA-MB-231 cells. In conclusion, NAM may be used as a chemo­ or radiosensitizing agent regardless of the BRCA1 status in breast cancer.