Genetic association signal near NTN4 in Tourette syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10⁻³) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry‐matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10⁻⁴) remained significant after Bonferroni correction. Meta‐analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10⁻⁷). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case–control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. Ann Neurol 2014;76:310–315     

Vessel co‐option is common in human lung metastases and mediates resistance to anti‐angiogenic therapy in preclinical lung metastasis models

Anti‐angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti‐angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre‐existing vessels from surrounding tissue (vessel co‐option). As anti‐angiogenic therapies were designed to target only new blood vessel growth, vessel co‐option has been proposed as a mechanism that could drive resistance to anti‐angiogenic therapy. However, vessel co‐option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti‐angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co‐option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co‐opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co‐opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co‐option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co‐option mediates resistance to the anti‐angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co‐option in lung metastases occurs through at least three distinct mechanisms, that vessel co‐option occurs frequently in lung metastases, and that vessel co‐option could mediate resistance to anti‐angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co‐option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

A Comparison of Three Nickel Titanium Rotary Systems,EndoSequence, ProTaper Universal,and Profile GT,for Canal-cleaning Ability

Canal preparation is a major step in root canal treatment and is directly related to subsequent disinfection and obturation. In recent years, nickel-titanium rotary systems such as the EndoSequence (Brassler USA, Savannah, GA), the ProTaper Universal (Dentsply/Maillefer, Ballagigues, Switzerland), and the ProFile GT (Dentsply/Maillefer, Ballagigues, Switzerland) have significantly altered root canal instrumentation. EndoSequence has become a very popular system among general practitioners but has not been scientifically tested or compared with other rotary systems that are commonly used by both specialists and general practitioners. The purpose of this study was to compare cleaning effectiveness under scanning electron microscopy (SEM) using three different rotary nickel-titanium instruments: the ProTaper variable taper, the ProFile GT .04 taper, and the EndoSequence .04 taper. Thirty-six extracted mandibular molars were selected for this study. The teeth were randomly divided into three groups. Each group had two noninstrumented teeth that served as controls. All teeth were prepared to a #40 final apical file after manufacturers' instructions. All three systems were used in the traditional “crown-down technique.” Teeth were sectioned buccolingually and examined under SEM at 20.0 kV and 500× magnification in the middle third of the canal. Debris was defined as dentin chips, pulp remnants, and particles loosely attached to the root canal wall. Analysis of the SEM images was performed by using a five-score index. Results indicated that there was no difference in cleansing ability of the three file types.     

Erratum: Exploring the clinical and social determinants of prescribing anticholinergic medication for Chinese patients with schizophrenia

Human Psychopharmacology 2007; 22 : 173–180 DOI: 10.1002/hup.830 It has come to our attention that there was an error to one of the author names within this published article. The correct author listing and author affiliation is now published below. We apologise for this anomaly. Xiang Yu‐Tao^1,2, Weng Yong‐Zhen², Leung Chi‐Ming¹, Tang Wai‐Kwong¹, Ungvari Gabor Sandor^{1 1}Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China ²Beijing Anding Hospital, Capital Medical University, Beijing, China     

Role of prenatal detection of cardiac tumours in the diagnosis of tuberous sclerosis--report of two cases

Tuberous sclerosis is an autosomal dominant disease with variable expression. Little is known about the intrauterine course of the disease and the fetal age at which specific abnormalities may be detected. The role of prenatal detection of cardiac tumours in the diagnosis of two fetuses at 28 and 32 weeks' gestation based on fetal echocardiography is discussed. The prenatal and postnatal course of the disease is described.     

Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease

Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.     

Non-competitive AMPA antagonists of 2,3-benzodiazepine type

The discovery of the selective AMPA antagonist character of 2,3-benzodiazepine derivative GYKI 52466 (5) in the late eighties and the recognition of the non-competitive nature of its mode of action some years later set off the world-wide search for novel class of drugs. Notably the quest to develop new antiepileptic and neuroprotective medicines, which allosterically inhibit the AMPA sensitive glutamate operated channels. This review summarises our present knowledge about the allosteric site, dubbed "GYKI site" where the 2,3-benzodiazepines are supposed to bind to. The structure-activity relationships among AMPA antagonist 2,3-benzodiazepines and their structural analogues with similar biological profile are reviewed in a possibly comprehensive fashion. The chemical synthesis of 2,3-benzodiazepines is shortly described. The in vitro and in vivo experimental methods used for pharmacological characterisation of the biologically active compounds are briefly explained. Finally the therapeutic potential of 2,3-benzodiazepines i.e. the main fields of their clinical utility are outlined with special regard to talampanel (20) in the light of the ongoing clinical trials with this new drug candidate.     

The feasibility and accuracy of diagnostic laparoscopy in the septic ICU patientrid=""id=""Presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), San Antonio, Texas, USA, 24–27 March 1999

BACKGROUND: Systemic inflammatory response syndrome (SIRS) and sepsis of unknown origin are common complications of critically ill patients in the ICU. These patients frequently have unreliable clinical exams and are candidates for exploratory laparotomy. Although abdominal CT is commonly used because it is less invasive than laparotomy, it is often unreliable or unobtainable. Bedside laparoscopy is an alternative technique that may be more accurate than CT in selected patients and less invasive than laparotomy. METHODS: We performed diagnostic laparoscopy (DL) in a series of ICU patients with SIRS/septic state of unknown origin between May 1997 and June 1998. All patients were unstable and required significant respiratory and hemodynamic support. Laparoscopy was either performed in the ICU at the patient's bedside or in the operating room. CT scan of the abdomen had been performed on most of the patients who were stable enough to transport. Confirmation of diagnosis was obtained either by laparotomy, autopsy, or clinical recovery. RESULTS: Among the 17 eligible patients, 16 underwent successful DL. Insufflation was impossible in one patient because of high intraabdominal pressure. Bedside evaluations were performed in 14 of the 17 patients. There were no complications from the laparoscopy. Six patients were identified as positive (four intestinal ischemia, two cholecystitis); the other 10 had negative explorations. Follow-up on two patients with negative laparoscopy was incomplete due to denied postmortem. Laparoscopic diagnoses were confirmed in the remaining 14 patients by laparotomy (six cases), postmortem (three cases), or recovery (five cases), with an accuracy of 100%. The overall accuracy of abdominal CT obtained in nine of the 14 patients was 33%. CONCLUSIONS: DL in a select group of critical ICU patients is safe and accurate, whereas CT scan tends to be inaccurate and is often unobtainable due to patient instability. Performing the procedure at the bedside can expedite the diagnosis, eliminate the burden for transfer, and save on anesthesia and operating room charges.     

Double-blind placebo-controlled trial of corticosteroids in children with postpericardiotomy syndrome

Summary The objective of this study was to assess the efficacy of corticosteroids in hastening the recovery of children with postpericardiotomy syndrome, using a randomized double-blind placebo-controlled trial in a tertiary care referral center for pediatric cardiology and cardiac surgery. Twenty-one children, 6 months of age or older (mean age 3.9 years) with postpericardiotomy syndrome following open or closed heart surgery were administered either prednisone 2 mg/kg/day reducing to zero over 14 days (n=12) or placebo (n=9). Progress was monitored by daily clinical assessment and alternate day cross-sectional echocardiograms. The primary measures of efficacy were the number of patients in remission at 72 h and at 1 week. No difference in remission rates were found at 72 h, but at 1 week significantly more children treated with prednisone were in remission (placebo 3/9; prednisone 10/12,p=0.03). A trend to faster resolution of all symptoms and signs was seen in the prednisone-treated group but this was not associated with earlier hospital discharge. Enlargement of pericardial effusion was seen in two children treated with steroids. No complications of treatment were encountered. Prednisone hastens the recovery of children with postopericardiotomy syndrome. Pericardial effusions may increase in size despite the use of corticosteroids.Presented in part at the Society for Pediatric Research, New Orleans, May 1991.