1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.     

Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide

Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.     

Tissue-conserving surgery for prognosis,treatment, and function preservation

Objectives: To describe an approach based on initial tissue-conserving surgery used to obtain histologically determined prognostic information that has therapeutic implications and the potential to enhance preservation of function. Study Design: Analysis of a group of patients with head and neck cancer treated initially with tissue-conserving surgery based on Mohs' histographic sectioning and selected neck dissection to derive histologically determined prognostic information with therapeutic implications and preservation in function. Methods: This study is primarily based on an analysis of patients from January 1, 1989, through June 4, 1996 assigned to a protocol evaluating resection of oral cavity squamous cell cancer with margin control using Mohs' histographic technique and/or a group of patients with neck assessment of N0 on clinical examination who are undergoing supraomohyoid neck dissections. Results: Thirty-three primary tumor resections were performed using the Mohs' technique, and 54% required two or more Mohs' sections before clear histologic margins were obtained following resection based on clinically determined negative margins. There were 44 patients who underwent unilateral or bilateral supraomohyoid neck dissections, and 33% had occult, histologically positive nodes. When compared with the disease of the neck specimens, a preoperative computed tomography scan had a sensitivity of 25%, a specificity of 77%, and an accuracy of 63%. Conclusions: This report describes the effectiveness of Mohs' histographic sectioning and selective neck dissection as a means of determining prognostic information that can be used to develop a focused and cost-effective treatment program that, along with contemporary reconstructive techniques, provides a potential enhancement of function preservation. Laryngoscope, 108:1599–1604, 1998     

Expression of cytochrome p450 and other biotransformation genes in fetal and adult human nasal mucosa.

Despite recent progress in the identification and characterization of numerous nasal biotransformation enzymes in laboratory animals, the expression of biotransformation genes in human nasal mucosa remains difficult to study. Given the potential role of nasal biotransformation enzymes in the metabolism of airborne chemicals, including fragrance compounds and therapeutic agents, as well as the potential interspecies differences between laboratory animals and humans, it would be highly desirable to identify those biotransformation genes that are expressed in human nasal mucosa. In this study, a global gene expression analysis was performed to compare biotransformation enzymes expressed in human fetal and adult nasal mucosa to those expressed in liver. The identities of a list of biotransformation genes with apparently nasal mucosa-selective expression were subsequently confirmed by RNA-polymerase chain reaction (PCR) and DNA sequencing of the PCR products. Further quantitative RNA-PCR experiments indicated that, in the fetus, aldehyde dehydrogenase 6 (ALDH6), CYP1B1, CYP2F1, CYP4B1, and UDP glucuronosyltransferase 2A1 are expressed preferentially in the nasal mucosa and that ALDH7, flavin-containing monooxygenase 1, and glutathione S-transferase P1 are at least as abundant in the nasal mucosa as in the liver. The nasal mucosal expression of CYP2E1 was also detected. These findings provide a basis for further explorations of the metabolic capacity of the human nasal mucosa for xenobiotic compounds.     

Cognitive improvement in schizophrenic patients does not require a serotonergic mechanism: randomized controlled trial of olanzapine vs amisulpride.

Combined serotonin-2A (5-HT(2A)) and dopamine-2 (D2) receptor blockade has been proposed as a candidate mechanism by which second-generation antipsychotics (SGAs) improve both cognition and negative symptoms in schizophrenic patients, in contrast to antipsychotics of the first generation. The SGA amisulpride, however, only binds to D2/D3 receptors, which makes it an interesting tool to test this assumption. In a randomized controlled trial, 52 schizophrenic patients were allocated to treatment with either olanzapine (10-20 mg/day) or amisulpride (400-800 mg/day). A comprehensive neuropsychological test battery and clinical ratings were used to assess participants at inclusion and after 4 and 8 weeks. Cognitive improvements of moderate size were observed, with effect sizes similar to those obtained in previous studies on the cognitive effects of SGAs. Importantly, amisulpride was not inferior to olanzapine for any cognitive domain. Combined 5-HT(2A)/D2 receptor blockade is probably not necessary for cognitive improvement by SGAs.     

Neural processing associated with cognitive empathy in pedophilia and child sexual offending

Behavioral studies found evidence for superior cognitive empathy (CE) in pedophilic men without a history of child sexual offending (P − CSO) compared to pedophilic men with a history of child sexual offending (P + CSO). Functional magnetic resonance imaging (fMRI) studies also point to differences between P − CSO and P + CSO. Neural processing associated with CE has not yet been investigated. Therefore, the present study aimed to explore the neural correlates of CE in subjects with pedophilia with (P + CSO) and without (P − CSO) child sexual offending. 15 P + CSO, 15 P − CSO and 24 teleiophilic male controls (TC) performed a CE task during fMRI. We observed reduced activation in the left precuneus (Pcu) and increased activation in the left anterior cingulate cortex (ACC) in P − CSO compared to P + CSO. P − CSO also showed stronger connectivity between these regions, which might reflect a top-down modulation of the Pcu by the ACC toward an increased self-focused emotional reaction in social situations. There was also evidence for increased right superior temporal gyrus activation in P − CSO that might constitute a potentially compensatory recruitment due to the dampened Pcu activation. These findings provide first evidence for altered neural processing of CE in P − CSO and underline the importance of addressing CE in pedophilia and CSO in order to uncover processes relevant to effective prevention of child sexual abuse.     

Evaluation of continuous aspiration of subglottic secretions in prevention of microaspiration during general anesthesia: a randomized controlled pilot study

AimTo assess the difference between endotracheal tubes (ETT) with continuous suction of subglottic secretions (CASS) and standard ETT in preventing secretions movement from the pharynx into the trachea, past the inflated cuff during general anesthesia.MethodsThis randomized, controlled trial enrolled 50 patients who underwent general anesthesia for elective abdominal surgery lasting longer than two hours. They received either ETT with CASS: Teleflex ISIS HVT (GISIS, n = 17) or Mallinckrodt TaperGuard Evac (GEvac, n = 17), or ETT without suction: Mallinckrodt Intermediate Hi-Lo (GStand, n = 16). Methylene blue dye solution (10 mL) was delivered into the hypopharynx every 60 minutes. Subglottic secretions were continuously suctioned. Fiberoptic bronchoscopy was performed every 20 minutes and during tracheal extubation to evaluate the dye location.ResultsThe groups did not differ in age, sex, body mass index, race, American Society of Anesthesiologists status, and surgery type. Dye migrated past the inflated cuff into the distal trachea in no patient with ETT with CASS and in 13% of patients with standard ETT. On tracheal extubation, dye migrated into the distal trachea more often in the GStand group (56%), compared with the GEvac (13%) and GISIS group (29%) (P = 0.045). The GISIS group had 26 ± 19 mL of secretions suctioned from above the inflated cuff, while the GEvac group had 13 ± 10 mL (P = 0.05).ConclusionCompared with standard ETT, ETT with CASS efficiently removed secretions during general anesthesia, prevented secretions from migrating past the inflated cuff, and significantly reduced the amount of secretions that reached the distal airways on tracheal extubation.ClinicalTrial.gov identification number{"type":"clinical-trial","attrs":{"text":"NCT01386879","term_id":"NCT01386879"}}NCT01386879

Postoperative pulmonary complications (PPC) commonly lead to morbidity and mortality in patients managed with general anesthesia for major surgery. In a systematic review of PPC after non-cardiothoracic surgery, the average incidence was 3.4% with a range from 1% to over 40% (1). Elderly and diabetic patients had the highest incidence. The incidence in abdominal surgery was 14.2% (1). A prospective multicenter study with a heterogeneous surgical population of almost 2500 patients revealed a 5.0% incidence of PPC; with a high mortality in patients who developed PPC (2). Patients with evidence of microaspiration have about three times higher incidence of postoperative pneumonia compared with patients without microaspiration (40% vs 12%), with mortality rate of 19.2% if they develop pneumonia (3).Endotracheal tubes (ETT) with continuous aspiration of subglottic secretions (CASS) are recommended in intensive care unit (ICU) patients requiring prolonged mechanical ventilation to prevent ventilator-associated pneumonia (4). A meta-analysis showed almost a 50% reduction of ventilator-associated pneumonia in patients receiving ETT with CASS in the ICU compared with standard ETT (5). It is unknown if using an ETT with CASS intraoperatively reduces the incidence of PPC in patients undergoing prolonged general anesthesia, and are extubated at the end of surgery.We hypothesized that a subglottic suction ETT with CASS would effectively remove secretions that accumulate above the inflated cuff and decrease the volume of secretions aspirated into the distal trachea during general anesthesia with mechanical ventilation and during tracheal extubation. The primary aim of the study was to evaluate whether there is a difference between three types of ETT in preventing the movement of methylene blue dye from the pharynx into the trachea, past the inflated cuff. The secondary objectives were to evaluate whether there is a difference in the volume, pH, and bacterial load of the secretions aspirated from above the subglottic suction ETT cuff.     

Theoretical and Experimental Models to Evaluate the Possibility of Corrosion Resistant Concrete for Coastal Offshore Structures

This study built theoretical and practical models to evaluate the corrosion resistance of concrete for coastal offshore structures in Vietnam. A mathematical model was developed in the form of a system of nonlinear partial differential equations characterizing the diffusion “free calcium hydroxide” in a solid of a concrete structure. The model describes the process of non-stationary mass conductivity observed in the “concrete structure—marine environment” system under non-uniform arbitrary initial conditions, as well as combined boundary conditions of the second and third kind, taking into account the nonlinear nature of the coefficients of mass conductivity k and mass transfer β. It was shown that the solution of the boundary value problem of non-stationary mass conductivity allows us to conclude about the duration of the service life of a concrete structure, which will be determined by the processes occurring at the interface: in concrete—mass conductivity, depending on the structural and mechanical characteristics of hydraulic structures, and in the liquid phase—mass transfer, determined by the conditions of interaction at the interface of the indicated phases.