Survey of imposex in Nucella lapillus as an indicator of tributyltin pollution in Northern Irish coastal waters, 2004 to 2017.

Tributyltin (TBT) was a commonly used biocide in anti-fouling paints for marine vessels, however, it had negative impacts on non-target species, including causing imposex in dogwhelks (Nucella lapillus). Since the 1980s, legislation has been introduced to curtail its usage, culminating in a ban by the International Maritime Organisation (IMO) in 2008. In 2004 a national imposex monitoring network was established in Northern Ireland to determine the level and extent of TBT pollution. The level of imposex in N. lapillus was assessed according to the degree of male sexual development in the female using three measures: percentage of imposex-affected females (%I), the relative penis size index (RPSI), and the vas deferens sequence index (VDSI). All sites showed improvement since the initial survey with a reduction in imposex and an improvement in ecological quality under the classification of the Convention for the Protection of the Marine Environment of the North-East Atlantic (OSPAR).

Increased Water Content in Periventricular Caps in Patients without Acute Hydrocephalus.

BACKGROUND AND PURPOSE: Periventricular caps are a common finding on MR imaging and are believed to reflect focally increased interstitial water content due to dysfunctional transependymal transportation rather than ischemic-gliotic changes. We compared the quantitative water content of periventricular caps and microvascular white matter lesions, hypothesizing that periventricular caps associated with increased interstitial fluid content display higher water content than white matter lesions and are therefore differentiable from microvascular white matter lesions by measurement of the water content. MATERIALS AND METHODS: In a prospective study, we compared the water content of periventricular caps and white matter lesions in 50 patients using a quantitative multiple-echo, gradient-echo MR imaging water-mapping sequence. RESULTS: The water content of periventricular caps was significantly higher than that of white matter lesions (P = .002). Compared with normal white matter, the mean water content of periventricular caps was 17% ± 5% higher and the mean water content of white matter lesions was 11% ± 4% higher. Receiver operating characteristic analysis revealed that areas in which water content was 15% higher compared with normal white matter correspond to periventricular caps rather than white matter lesions, with a specificity of 93% and a sensitivity of 60% (P < .001). There was no significant correlation between the water content of periventricular caps and whole-brain volume (P = .275), white matter volume (P = .243), gray matter volume (P = .548), lateral ventricle volume (P = .800), white matter lesion volume (P = .081), periventricular cap volume (P = .081), and age (P = .224). CONCLUSIONS: Quantitative MR imaging allows differentiation between periventricular caps and white matter lesions. Water content quantification of T2-hyperintense lesions may be a useful additional tool for the characterization and differentiation of T2-hyperintense diseases.

Preclinical predictors that the orthosteric mGlu2/3 receptor antagonist LY3020371 will not engender ketamine-associated neurotoxic, motor, cognitive, subjective, or abuse-liability-related effects.

The novel mGlu2/3 receptor antagonist, LY3020371, has been shown to produce antidepressant-like effects comparable to that of the clinically-effective antidepressant ketamine. In the present study, we investigated whether LY3020371 would be predicted to be free of the side-effects and safety pharmacology issues associated with ketamine. In contrast to ketamine, LY3020371 produced small increases in locomotion and did not impair motor performance on an inverted screen. Ketamine, but not LY3020371, increased dopamine efflux in the nucleus accumbens of rats. Ketamine also produced cognitively-impairing effects in rats in a T-maze and in a psychomotor vigilance task and altered theta synchrony between the hippocampus and mPFC, whereas LY3020371 had either no significant impact or lesser effects in these assays. In mice, ketamine, but not LY3020371, negatively affected spontaneous alternation in a Y-maze. Rats were trained to discriminate LY3020371 from vehicle where 30mg/kg produced 100% drug-appropriate responding and the ED50 for LY3020371 was 9.4mg/kg, i.p. In rats discriminating LY3020371, neither d-amphetamine nor phencyclidine fully substituted for LY3020371 (35-45%) and the mGlu2/3 receptor agonist LY354740 partially attenuated the discriminative stimulus effects of LY3020371. These are the first data to demonstrate the discriminative stimulus effects of an mGlu2/3 receptor antagonist. Some alterations were suggested to occur in the density of mGlu2/3 receptor binding sites in the drug discrimination rats relative to their age-matched non-drug-exposed controls. In preclinical toxicology studies of 14day dosing of doses up to 1000mg/kg, i.v. in rats and up to 500m/kg, i.v. in Cynomologous monkeys, LY3020371 produced uM plasma exposures without producing critical toxicological findings. It is concluded that LY3020371 does not recapitulate the motor, cognitive, subjective, neurochemical, electrophysiological, or toxicological findings reported with ketamine. Thus, LY3020371 possesses both the efficacy signatures of a rapidly-acting antidepressant and a safety profile enabling proof of concept studies in patients.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

BACKGROUND: Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. METHODS: Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). RESULTS: Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. CONCLUSIONS: These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity.

Success in crown and bridge work.

All practitioners wish for success in their restorative work mainly due to their desire to do the best for their patients, but increasingly the achievement of success, ie the avoidance of failure, is felt to be necessary to avoid the spectre of litigation. The number of patient-led litigation cases is on the increase and the majority involve crown and bridge work.

The time course of the hyperactivity that follows lesions or temporary inactivation of the fimbria-fornix.

Lesions of the hippocampus or the fimbria-fornix produce a pronounced hyperactivity in rats. This effect is thought to be due to the loss of glutamatergic hippocampal inputs to the nucleus accumbens, although the mechanisms involved remain unclear. It has been suggested that the hyperactivity is due to changes in accumbens dopamine receptors, possibly involving the gradual development of denervation supersensitivity. Consistent with this possibility, the present study found that fimbria-fornix transection produced hyperactivity which, although undetectable immediately after surgery, gradually became apparent and then continued to increase over the course of several days. This does not, however, preclude the possibility that there is an immediate increase in activity which is masked by the after effects of surgery. To address this issue, local anaesthetic was infused into the fimbria-fornix via chronic indwelling cannulae, in order to silence the hippocampal inputs to the nucleus accumbens. This procedure impaired spatial working memory on the elevated T-maze and resulted in immediate hyperactivity, suggesting that there may be at least two components to fornix lesion-induced hyperactivity, and that the immediate effects of mechanical fornix lesions on activity levels may be masked by the after effects of surgery per se.

Predictable resin-bonded bridges in general dental practice.

This paper discusses the use of resin-bonded bridges as predictable restorations in general dental practice. The importance and relevance of case selection is stressed. Efforts have been made to discuss ideal design features, creation of interocclusal space and the need to carry out any tooth preparations. In addition, the clinical stages involved are outlined and a brief comparison with conventional bridges and implant-retained prostheses made.

Hydrogen bonding in salicylsalicylic acid (salsalate) crystals.

An X-ray crystallographic study of the drug salsalicylic acid (salsalate) has been performed. Crystal formation of the drug is influenced by both inter- and intra-molecular hydrogen bonding. In addition an OH group in salsalate can occupy alternate ortho positions resulting in two hydrogen bonding motifs within a single crystal.

The role of nigral and thalamic output pathways in the expression of oral stereotypies induced by amphetamine injections into the striatum.

Microinjections of amphetamine into the ventrolateral striatum (VLS) elicit a striking behavioral syndrome characterized by compulsive oral and forelimb motor stereotypies. The neural pathways that mediate these behavioral responses downstream from the striatum have not yet been identified. In a series of experiments, we investigated the involvement of the substantia nigra pars reticulata (SNr) and the ventromedial nucleus of the thalamus (VMT) in the mediation of this behavioral syndrome. We demonstrated that lidocaine-induced reversible inactivation of the SNr reduced amphetamine-induced stereotyped biting and gnawing behaviors, suggesting that the nigral output pathway plays a significant role in the expression of these behavioral responses. In turn, injections of lidocaine into the VMT only transiently reduced amphetamine-stimulated biting and increased stereotyped gnawing and paw nibbling, suggesting that the expression of oral stereotypies induced by amphetamine injections into the VLS is not dependent on thalamocortical feedback.

Corneal melting after pterygium removal followed by topical mitomycin C therapy.

Right corneal melting and scleral necrosis developed in a 77-year-old man 5 months after pterygium excision followed by topical administration of mitomycin C drops (0.4 mg/mL) for 4 weeks. We believe that these were delayed complications of the mitomycin C therapy, and we caution against prolonged use of the drug postoperatively.

The assessment of diabetic control in insulin-independent patients.

All diabetics are at risk from the development of the specific and non-specific complications of the disorder. While good control with relative normoglycaemia may be beneficial, most of the emphasis on maintaining stricter blood glucose control has been aimed at the insulin-dependent diabetic. Seventy-four sylphonylurea-treated were observed for a year and their degree of control assessed and compared using simple clinical criteria, plasma glucose levels and haemoglobin A1c concentrations. Control was considered good in 55.4 per cent, 16.2 per cent and 14.9 per cent using each criterion respectively. Simple clinical assessment of control is therefore unlikely to achieve normoglycaemia in the majority of such patients. A more wide ranging assessment and a more aggressive approach to therapy may be desirable if better blood glucose control can be shown to produce a reduction in the significant morbidity and mortality in these patients.