Characterizing metabolites and potential metabolic pathways for the novel psychoactive substance methoxetamine.

The classic approach of controlled volunteer studies to study drug metabolism is difficult or impossible to undertake for novel psychoactive substances (NPS), as there is generally very limited information available to allow appropriate dose finding and safety. A viable and powerful alternative is the identification and characterization of phase I and II metabolites of such drugs by examining the concordance of data gathered from analysis of microsomal incubates with that from analysis of specimens collected from individuals with analytically confirmed use of NPS. Liquid chromatography-high resolution mass spectrometry provides the ability to reliably identify such metabolites. We used this technique here to study the metabolism of the ketamine analogue methoxetamine. A large number of metabolites were identified in the in vitro studies including normethoxetamine, O-desmethylmethoxetamine, dihydromethoxetamine, dehydromethoxetamine and several structural isomers of hydroxymethoxetamine and hydroxynormethoxetamine. pH dependent liquid-liquid extraction was used to discriminate phenolic from alcoholic metabolites. Phase II glucuronide conjugates included those of O-desmethylmethoxetamine, O-desmethylnormethoxetamine and O-desmethylhydroxymethoxetamine. The majority of these phase I and II metabolites were confirmed to be present in urine collected from three individuals presenting with acute methoxetamine toxicity.

The poppy seed defense: a novel solution.

A major toxicological challenge is distinguishing whether morphine in urine, in the absence of 6-monoacetylmorphine (6-MAM), originates from 'street' heroin use or poppy seed ingestion. Manufacturing byproducts from the synthesis of illicit heroin include those that originate from the reaction of acetic anhydride with the alkaloid impurity, thebaine, which undergoes skeletal rearrangement, resulting in compounds with a 2-(N-methylacetamido)ethyl side-chain. The hypothesis that the tertiary amide in this side-chain is resistant to endogenous hydrolysis was supported from in-vitro experiments; a glucuronide metabolite (designated 'ATM4G') was identified that may be used as a marker of 'street' heroin administration. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for this metabolite was then performed on selected urine specimens from 22 known heroin users, these being negative on routine testing for 6-MAM by gas chromatography-mass spectrometry (GC-MS), using the generally applied reporting threshold of 10 ng/mL, but positive for the presence of morphine. Peaks corresponding to the retention time for the metabolite marker were clearly observed for 16 of the 22 samples, with variations of the ratios of its three dependent ions being within ± 30% of that produced in vitro. Conversely, 6-MAM was detected in only 3 samples, but at concentrations <1 ng/mL. Such a high frequency for the presence of the metabolite marker in urine, in the absence of 6-MAM, is noteworthy and suggests that detection of this metabolite may offer an important advance in forensic toxicology, allowing the development of a new and more definitive test for heroin abuse and thus a potential solution to the so-called 'poppy seed defense'.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Dental observations of hyper IgE disorder.

Recognition of "Jobs Syndrome" disorder may lead to better care. One of the dental manifestations reported is a high arched palate. Measurements of the maxillary arch were made to compare affected Job's patients, unaffected family members, and controls. Measurements of the palate found little difference between the three groups. DMFS, periodontal disease, and oral hygiene were evaluated with little difference between groups.

An in-vitro comparison of the radiographic and actual gutta-percha terminus.

The purpose of this study was to investigate the difference between the radiographic gutta-percha terminus and the actual gutta-percha terminus of human molars by comparing radiographic obturation results with actual obturation results. Forty maxillary palatal roots and 50 mandibular distal roots were randomly selected from a population of 540. They were then mounted in stone and radiographed. Conventional endodontic therapy was completed using stainless-steel K files and lateral condensation. Each radiographic gutta-percha terminus was evaluated under 4.5x magnification by three examiners following the completion of root canal therapy. These results were recorded. Each tooth was then removed from its mounting, and the actual gutta-percha terminus was evaluated under 4.5x magnification. These results were recorded and compared to the radiographic gutta-percha terminus results. In all 90 teeth examined, the actual gutta-percha terminus was equal to or longer than the radiographic gutta-percha terminus. In the 50 mandibular distal roots, the actual gutta-percha terminus averaged 0.645 mm longer than the radiographic gutta-percha terminus. In the 40 maxillary palatal roots, this difference measured 0.6375 mm.

Comparison of the baroreceptor-heart rate reflex effects of moxonidine, rilmenidine and clonidine in conscious rabbits.

In 10 conscious rabbits, the baroreceptor-heart rate (HR) reflex effects of centrally acting antihypertensive agents with high affinity for imidazoline receptors (IRs), moxonidine and rilmenidine, were compared with clonidine which acts predominantly via central alpha2-adrenoceptors. Dose regimens were chosen to give similar hypotension (-17+/-1 mm Hg) and bradycardia (-27+/-2 b/min) for all three agents given into the fourth ventricle. Baroreceptor-HR reflex curves were assessed by i.v. drug induced changes in blood pressure. With all treatments, the baroreflex curves with both vagal and sympathetic effectors intact were shifted to the left, corresponding to the hypotension, and the bradycardia plateau was reduced. Rilmenidine and moxonidine also reduced the upper plateau such that the curves were shifted parallel down the HR scale with no change in the HR range. By contrast, clonidine only decreased the lower plateau, and thus increased HR range (+19+/-6%). Moxonidine, but not rilmenidine, reduced the baroreflex gain by reducing the curvature. Clonidine also decreased curvature but this did not result in a reduction in gain as it was offset by the increase in HR range. The gain and range of the cardiac sympathetic component, as assessed after vagal blockade, was reduced by rilmenidine by 53 and 40% respectively, but was not affected by the other agents. The calculated vagal component of the curves showed that all agents produced a greater vagal bradycardia in response to a rise in pressure and that both rilmenidine and clonidine increased vagal HR range. The present study results show that many of the baroreflex effects of clonidine, such as facilitating cardiac vagal responses, are shared by the second generation agent rilmenidine, suggesting that they are primarily due to alpha2-adrenoceptor activation. In addition, the inhibition of the sympathetic component of the baroreflex, observed with rilmenidine, and not clonidine suggests that this effect may involve IRs. By contrast moxonidine, the most specific agent for I1 receptors, produces mainly a baroreflex independent inhibition of cardiac sympathetic activity with little effect on vagal activity.

Osseointegration and growth effects of temporal bone percutaneous pedestals.

The percutaneous temporal bone pedestal has shown significant utility for the attachment of bone-anchored hearing aids, attachment of cosmetic auricular prostheses, and as connector between external sound processors and implanted cochlear implants. The biological acceptance of these implants by temporal bone hosts is affected by many factors including the maturity of the bone, the design of the pedestal-fixation system, and the pedestal-construction material. The first phase of this study evaluated the effect of the pyrolized graphite pedestal fixation on maturing temporal bones. Pedestals were implanted in young swine temporal bones using single screw and multiple screw fixation systems. The effect on temporal bone growth is demonstrated with photomicrographs and gross photography showing acceptable host-tissue response to the presence of multiple and single screw attachment techniques. Osseointegration of the attaching screws occurred. The second phase of the study evaluated osseointegration of smooth, beaded, and textured titanium pedestals in feline temporal bones. High-resolution temporal bone/pedestal sectioning has been accomplished with high-performance microtomes, showing the osseointegration of the pedestal by the temporal bone. This is demonstrated with tetracycline labeling and histologic assessment. Percutaneous pedestals are of increasing importance in otologic practice. This study assists in the understanding of biologic acceptance of pedestals as influenced by the pedestal composition and fixation design. This basic understanding is essential for design improvements in percutaneous temporal bone pedestals.

Elevation of cyclic AMP levels in mouse embryonic stem cells by insulin related peptides.

The preimplantation mammalian embryo has been shown to respond to exogenous insulin-like growth factors and insulin itself, however, the most quantitatively important source of these peptides and the receptors through which they exert their effects are unclear. Whilst the type 1 insulin-like growth factor (IGF) receptor is believed to act primarily through tyrosine phosphorylation of the substrate protein alpha IRS-1, evidence for a signalling role for the type 2 receptor is disputed, some evidence pointing to mediation through G protein-dependent calcium ion flux. We have examined the response of murine embryonic stem cells, as a model for the cells of the preimplantation embryo, to IGF-I, IGF-II, insulin and analogs of IGF-II: R6 IGF-II and des (1-6) IGF-II. In response to all of these peptides, except R6 IGF-II, elevation of intracellular cyclic AMP occurs. As R6 IGF-II binds with higher affinity to the type 2 receptor than canonical IGF-II or IGF-I, and insulin fails to interact, this suggests that the elevation of cyclic AMP in response to the other insulin related peptides (IRPs) is not through the type 2 receptor. We conclude that either the type 1 receptor has a previously uncharacterized direct or indirect effect on intracellular cyclic AMP levels, or that there is a further, as yet uncharacterized, receptor active in embryonic stem cells.

Insulin-related peptides and the two-cell block to development in pre-implantation mouse embryos.

In many mammalian embryos development in vitro is arrested after the first zygotic division, a phenomenon known as the two-cell block. In the mouse several strains exhibit a two-cell block to further development and it was the purpose of this investigation to determine whether the inability of embryos to progress through the block was due to lack of insulin or insulin-like growth factors (IGFs) in the medium. Several factors have been implicated in the two-cell block, amongst which oxidative stress, glucose and missing maternal factors have been examined to date. Because of their anabolic and anti-apoptotic properties, IGFs are good candidates for such missing maternal factors. Using MF1 strain mice and M16 medium we have examined the effects of IGF-I, II and insulin on the two-cell block. No effects were discernable at concentrations known to support development of non-blocking embryos and we conclude that the IGFs and insulin may be excluded as critical factors in the two-cell block under the culture conditions used.

Multichannel cochlear implantation with percutaneous pedestal.

In a prospective study by Cohen et al, the superiority of multichannel cochlear implant patient performance over single-channel cochlear implant performance was demonstrated. The Ineraid system described in this paper includes a percutaneous pedestal which has had a satisfactory patient experience. Only one pedestal removal has been necessary because of specific pedestal problems. Other less serious pedestal problems decrease in frequency with increasing time post-implantation. The auditory performance indicates significant communication skills improvement in patients with multichannel cochlear implants.

Mortality from melanoma in migrants to Australia: variation by age at arrival and duration of stay.

All death records in Australia during the period 1964-1985 were analyzed to compare mortality from melanoma in immigrants and Australian-born individuals, and to investigate changes in risk in the immigrants according to their duration of stay and age at arrival. About 450,000 deaths were from cancer, and risks of melanoma were estimated by logistic regression relative to those of the Australian-born, with deaths from other cancers used as controls. Estimates were adjusted for age at death, time period, birth cohort, and state of registration of death in Australia. Region of birth was defined as New Zealand, other Oceania, England, Ireland/Scotland/Wales (including Northern Ireland and the Republic of Ireland), Central Europe, Eastern Europe, Southern Europe, Western Asia, or Eastern Asia, bearing in mind that many migrants born in Asia were of European descent. Overall, migrants from outside Oceania were at lower risk than the Australian-born, and the lowest risks in males were in Southern Europeans and Eastern Asians, reflecting the protective effect of a darker complexion. Risk of melanoma was related both to duration of stay in Australia and to age at arrival; although their relative importance cannot be measured, the patterns of change suggested that childhood migration may be more important in determining risk than number of years in Australia. The authors believe this study to be based on the largest data set ever used in migrant studies, and note that the previously found differences in melanoma risk between immigrants and Australian-born remained after adjustment for major temporal and geographic confounders. The results confirm the importance of the interaction between environmental and genetic risk factors in the etiology of melanoma.

Opisthorchis viverrini infestation and endogenous nitrosamines as risk factors for cholangiocarcinoma in Thailand.

Cholangiocarcinoma (CCA) is one of the most common cancers in north-east Thailand and has been associated with infestation by the liver fluke Opisthorchis viverrini (OV). Two samples of 12-hr overnight urine (after dosing with proline and ascorbic acid or proline alone) were collected from 20 inhabitants from each of 5 contrasting incidence areas for CCA. The incidence of CCA was not correlated with either the amount of NPRO or other nitrosamino acids, endogenous nitrosation potential (difference in NPRO levels between proline dose and proline and ascorbic dose), or nitrate level. However, when urinary levels of nitrosamino acids were compared in subjects living in high-risk areas, subjects who were positive for OV antibody excreted significantly more (p less than 0.01) NPRO (12.3 +/- 18.7 micrograms/12 hr) after proline ingestion than those who were negative (3.5 +/- 3.2 micrograms/12 hr). After ingestion of ascorbic acid, the NPRO levels in the positive subjects were significantly reduced (p less than 0.01) to 2.4 +/- 2.0 micrograms/12 hr, suggesting that endogenous nitrosation of proline was inhibited. Thus, endogenous nitrosation potential estimated from the difference between NPRO and the sum of nitrosamino acids excreted in the 2 urine samples was significantly higher in subjects positive for the OV antibody. Small amounts of pre-formed nitrosamines were found in fermented fish and pork food items, which are consumed frequently in the high-risk area for CCA. These results suggest that the interaction between chemical carcinogens, especially nitrosamines, and OV infestation may play a role in the development of cholangiocarcinoma in Thailand.

Endogenous nitrosamines and liver fluke as risk factors for cholangiocarcinoma in Thailand.

Cholangiocarcinoma (CCA) is one of the most prevalent cancers in north-east Thailand and has been associated with infestation by the liver fluke Opisthorchis viverrini (OV). Two samples of 12-h overnight urine (after dosing with 500 mg proline and 200 mg ascorbic acid or 500 mg proline alone) were collected from about 100 inhabitants in five contrasting incidence areas for CCA and hepatocellular carcinoma. The incidences of CCA and hepatocellular carcinoma were not correlated with either the amount of NPRO or other nitrosamino acids, endogenous nitrosation potential (difference in NPRO levels between proline dose and proline and ascorbic acid dose), or nitrate level. However, when urinary levels of nitrosamino acids were compared in subjects living in high-risk areas, subjects who were positive for OV antibody excreted significantly more (p less than 0.01) NPRO (12.3 +/- 18.7 micrograms/12 h) after proline ingestion than those who were negative 3.5 +/- 3.2 micrograms/12 h). After ingestion of ascorbic acid, the NPRO levels in the positive subjects were significantly reduced (p less than 0.01) to 2.4 +/- 2.0 micrograms/12 h, suggesting that endogenous nitrosation of proline was inhibited. Thus, endogenous nitrosation potential estimated from the difference of NPRO and sum of nitrosamino acids excreted in the two urine samples was significantly higher in subjects positive for the OV antibody. In addition, of the representative food samples and beverages consumed frequently in high-risk areas for CCA, fermented fish and pork contained N-nitrosodimethylamine (0-26 micrograms/kg), N-nitrosopyrrolidine (0-117 micrograms/kg) and N-nitrosopiperidine (0-23 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

[Incidence of cancer in children throughout the world]. / L'incidence des cancers de l'enfant dans le monde.

The International Agency for Research on Cancer has coordinated a worldwide study of the incidence of cancer in childhood. Contributors from over 50 countries have provided data. This paper presents a summary of some of the major results. The incidence rates and relative frequencies of childhood cancers are described according to 12 diagnostic groups, defined mainly in terms of tumour morphology. Variations in the risk of those tumours between different countries and different ethnic groups provide important information on the relative importance of environmental and genetic factors in their aetiology.

Symmetry theorems on the forward and backward scattering Mueller matrices for light scattering from a nonspherical dielectric scatterer.

The symmetry theorems on the complete forward and backward scattering Mueller matrices for light scattering from a single dielectric scatterer (as opposed to an ensemble of scatterers) are systematically and thoroughly analyzed. Symmetry operations considered include discrete rotations about the incident direction and mirror planes not coinciding with the scattering plane. For forward scattering we find sixteen different symmetry shapes (not including the totally asymmetric one), which may be classified into five symmetry classes, with identical reductions in the forward scattering matrices for all symmetry shapes that fall into the same symmetry class. For backward scattering we find only four different symmetry shapes, which may be classified into only two symmetry classes. The forward scattering symmetry theorems also lead to a symmetry theorem on the total extinction cross section. Based on the conclusions of this work it should be possible to design quick and nondestructive methods for the identification of certain small objects, when suitable partial information about the objects to be identified is already available. A promising practical example is given.

Mueller matrix calculations for dielectric cubes: comparison with experiments.

A new resolvent kernel method is presented for solving the problem of electromagnetic scattering from irregular homogeneous particles. This method has an advantage over other methods in that an integrodifferential equation with a simple initial condition is solved to give a resolvent kernel matrix for a complete range of refractive indices for a fixed particle size. This matrix can then be used to calculate both near and far fields for any incident wave. Results are presented for a homogeneous cube in random orientation and compared with microwave analog measurements.

Albumin excretion in children and adolescents with insulin-dependent diabetes.

Microalbuminuria has been shown to predict end-stage renal failure in adults with insulin-dependent diabetes. We have measured albumin excretion rates (AER) in 106 normal adults, 64 normal children and 68 children with insulin-dependent diabetes. The median AER's in both groups of children were similar and both were significantly lower than in the adult population. In normal and diabetic children there was a significant positive correlation of AER with age, but not with duration of disease or HbA1 in the diabetic group. We conclude that AER is lower in children than in adults and that the levels of albumin excretion which are predictive of clinical diabetic nephropathy in adults may not be applicable to children.