DNA metabarcoding reveals the dietary profiles of a benthic marine crustacean, Nephrops norvegicus.

Norwegian lobster, Nephrops norvegicus, are a generalist scavenger and predator capable of short foraging excursions but can also suspension feed. Existing knowledge about their diet relies on a combination of methods including morphology-based stomach content analysis and stable isotopes, which often lack the resolution to distinguish prey items to species level particularly in species that thoroughly masticate their prey. DNA metabarcoding overcomes many of the challenges associated with traditional methods and it is an attractive approach to study the dietary profiles of animals. Here, we present the diet of the commercially valuable Nephrops norvegicus using DNA metabarcoding of gut contents. Despite difficulties associated with host amplification, our cytochrome oxidase I (COI) molecular assay successfully achieves higher resolution information than traditional approaches. We detected taxa that were likely consumed during different feeding strategies. Dinoflagellata, Chlorophyta and Bacillariophyta accounted for almost 50% of the prey items consumed, and are associated with suspension feeding, while fish with high fisheries discard rates were detected which are linked to active foraging. In addition, we were able to characterise biodiversity patterns by considering Nephrops as natural samplers, as well as detecting parasitic dinoflagellates (e.g., Hematodinium sp.), which are known to influence burrow related behaviour in infected individuals in over 50% of the samples. The metabarcoding data presented here greatly enhances a better understanding of a species' ecological role and could be applied as a routine procedure in future studies for proper consideration in the management and decision-making of fisheries.

Distinguishing Authentic Voices in the Age of ChatGPT: Comparing AI-Generated and Applicant-Written Personal Statements for Plastic Surgery Residency Application.

BACKGROUND: ChatGPT, a generative artificial intelligence model, may be used by future applicants in the plastic surgery residency match. METHODS: Ten personal statements (5 generated by ChatGPT, 5 written by applicants) were rated by 10 reviewers, blinded to the source of the essay. RESULTS: A total of a 100 evaluations were collected. There was no significant difference in ratings for readability, originality, authenticity, and overall quality (all P > 0.05) when comparing computer-generated and applicant essays. CONCLUSION: Personal statements prepared by ChatGPT are indistinguishable from essays written by actual applicants. This finding suggests that the current plastic surgery application format be reevaluated to better aid in holistic evaluation of students.

Risk factors for Epstein Barr virus-associated cancers: a systematic review, critical appraisal, and mapping of the epidemiological evidence.

BACKGROUND: Epstein Barr Virus (EBV) infects 90%-95% of all adults globally and causes ~ 1% of all cancers. Differing proportions of Burkitt's lymphoma (BL), gastric carcinoma (GC), Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC) are associated with EBV. We sought to systematically review the global epidemiological evidence for risk factors that (in addition to EBV) contribute to the development of the EBV-associated forms of these cancers, assess the quality of the evidence, and compare and contrast the cancers. METHODS: MEDLINE, Embase and Web of Science were searched for studies of risk factors for EBV-associated BL, GC, HL and NPC without language or temporal restrictions. Studies were excluded if there was no cancer-free comparator group or where analyses of risk factors were inadequately documented. After screening and reference list searching, data were extracted into standardised spreadsheets and quality assessed. Due to heterogeneity, a narrative synthesis was undertaken. RESULTS: 9916 hits were retrieved. 271 papers were retained: two BL, 24 HL, one GC and 244 NPC. The majority of studies were from China, North America and Western Europe. Risk factors were categorised as dietary, environmental/non-dietary, human genetic, and infection and clinical. Anti-EBV antibody load was associated with EBV-associated GC and BL. Although the evidence could be inconsistent, HLA-A alleles, smoking, infectious mononucleosis and potentially other infections were risk factors for EBV-associated HL. Rancid dairy products; anti-EBV antibody and EBV DNA load; history of chronic ear, nose and/or throat conditions; herbal medicine use; family history; and human genetics were risk factors for NPC. Fresh fruit and vegetable and tea consumption may be protective against NPC. CONCLUSIONS: Many epidemiological studies of risk factors in addition to EBV for the EBV-associated forms of BL, GC, HL and NPC have been undertaken, but there is a dearth of evidence for GC and BL. Available evidence is of variable quality. The aetiology of EBV-associated cancers likely results from a complex intersection of genetic, clinical, environmental and dietary factors, which is difficult to assess with observational studies. Large, carefully designed, studies need to be strategically undertaken to harmonise and clarify the evidence. REGISTRATION: PROSPERO CRD42017059806.

Consensus recommendations for resistance testing in the management of chronic hepatitis C virus infection: Public Health England HCV Resistance Group.

The treatment of hepatitis C virus (HCV) infection has been revolutionised by the advent of oral, well-tolerated, direct acting antiviral therapies (DAA), with high cure rates. However, in some scenarios, HCV resistance to antiviral therapies may have an impact on treatment success. Public Health England's HCV Resistance Group was established to support clinicians treating people with HCV, where the issue of resistance may be a factor in clinical decision-making, and this review includes the Group's current recommendations on the use of HCV resistance testing. The authors describe the principles behind and approach to HCV resistance testing and consider evidence from in vitro studies, clinical trials and real world cohorts on the impact of HCV resistance on treatment outcomes for particular DAA regimens. Five scenarios are identified in the UK and similar settings, where, in the Group's opinion, resistance testing should be performed.

Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

Pollen flow and paternity in an isolated and non-isolated black walnut (Juglans nigra L.) timber seed orchard.

Artificial pollination of black walnut (Juglans nigra L.) is not practical and timber breeders have historically utilized only open-pollinated half-sib families. An alternate approach called "breeding without breeding," consists of genotyping open-pollinated progeny using DNA markers to identify paternal parents and then constructing full-sib families. In 2014, we used 12 SSR markers to genotype 884 open-pollinated half-sib progeny harvested from two clonal orchards containing 206 trees, comprised of 52 elite timber selections. Seed was harvested in 2011 from each of two ramets of 23 clones, one upwind and one downwind, based on prevailing wind direction from the west-southwest. One orchard was isolated from wild black walnut and composed of forward selections while the other orchard was adjacent to a natural forest containing mature black walnut composed of backward selections. Isolation significantly increased within-orchard pollination (85%) of the progeny from the isolated orchard compared to 42% from the non-isolated orchard. Neither prevailing wind direction nor seed tree position in the orchard affected paternity patterns or wild pollen contamination. Genetic diversity indices revealed that progeny from both orchards were in Hardy-Weinberg equilibrium with very little inbreeding and no selfing. A significant level of inbreeding was present among the forward selected parents, but not the first generation (backward selected) parents. Some orchard clones failed to sire any progeny while other clones pollinated upwards of 20% of progeny.

Covalency and Ionicity Do Not Oppose Each Other-Relationship Between Si-O Bond Character and Basicity of Siloxanes.

Covalency and ionicity are orthogonal rather than antipodal concepts. We demonstrate for the case of siloxane systems [R3 Si-(O-SiR2 )n -O-SiR3 ] that both covalency and ionicity of the Si-O bonds impact on the basicity of the Si-O-Si linkage. The relationship between the siloxane basicity and the Si-O bond character has been under debate since previous studies have presented conflicting explanations. It has been shown with natural bond orbital methods that increased hyperconjugative interactions of LP(O)→σ*(Si-R) type, that is, increased orbital overlap and hence covalency, are responsible for the low siloxane basicity at large Si-O-Si angles. On the other hand, increased ionicity towards larger Si-O-Si angles has been revealed with real-space bonding indicators. To resolve this ostensible contradiction, we perform a complementary bonding analysis, which combines orbital-space, real-space, and bond-index considerations. We analyze the isolated disiloxane molecule H3 SiOSiH3 with varying Si-O-Si angles, and n-membered cyclic siloxane systems Si2 H4 O(CH2 )n-3 . All methods from quite different realms show that both covalent and ionic interactions increase simultaneously towards larger Si-O-Si angles. In addition, we present highly accurate absolute hydrogen-bond interaction energies of the investigated siloxane molecules with water and silanol as donors. It is found that intermolecular hydrogen bonding is significant at small Si-O-Si angles and weakens as the Si-O-Si angle increases until no stable hydrogen-bond complexes are obtained beyond φSiOSi =168°, angles typically displayed by minerals or polymers. The maximum hydrogen-bond interaction energy, which is obtained at an angle of 105°, is 11.05 kJ mol-1 for the siloxane-water complex and 18.40 kJ mol-1 for the siloxane-silanol complex.

Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential.

Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases. Here we use a pharmaceutical screen to discover new mechanisms for activation of autophagy. We identify a subset of pharmaceuticals inducing autophagic flux with effects in diverse cellular systems modelling specific stages of several human diseases such as HIV transmission and hyperphosphorylated tau accumulation in Alzheimer's disease. One drug, flubendazole, is a potent inducer of autophagy initiation and flux by affecting acetylated and dynamic microtubules in a reciprocal way. Disruption of dynamic microtubules by flubendazole results in mTOR deactivation and dissociation from lysosomes leading to TFEB (transcription factor EB) nuclear translocation and activation of autophagy. By inducing microtubule acetylation, flubendazole activates JNK1 leading to Bcl-2 phosphorylation, causing release of Beclin1 from Bcl-2-Beclin1 complexes for autophagy induction, thus uncovering a new approach to inducing autophagic flux that may be applicable in disease treatment.

Dissolution of tablet-in-tablet formulations studied with ATR-FTIR spectroscopic imaging.

This work uses ATR-FTIR spectroscopic imaging to study the dissolution of delayed release and pH resistant compressed coating pharmaceutical tablets. Tablets with an inner core and outer shell were constructed using a custom designed compaction cell. The core of the delayed release tablets consisted of hydroxypropyl methylcellulose (HPMC) and caffeine. The shell consisted of microcrystalline cellulose (MCC) and glucose. The core of the pH resistant formulations was an ibuprofen and PEG melt and the shell was constructed from HPMC and a basic buffer. UV/vis spectroscopy was used to monitor the lag-time of drug release and visible optical video imaging was used as a complementary imaging technique with a larger field of view. Two delayed release mechanisms were established. For tablets with soluble shell sections, lag-time was dependent upon rapid shell dissolution. For tablets with less soluble shells, the lag-time was controlled by the rate of dissolution medium ingress through the shell and the subsequent expansion of the wet HPMC core. The pH resistant formulations prevented crystallization of the ibuprofen in the core during dissolution despite an acidic dissolution medium. FTIR imaging produced important information about the physical and chemical processes occurring at the interface between tablet sections during dissolution.

Field-scale transport and transformation of carboxymethylcellulose-stabilized nano zero-valent iron.

The fate of nano zerovalent iron (nZVI) during subsurface injection was examined using carboxymethylcellulose (CMC) stabilized nZVI in a very large three-dimensional physical model aquifer with detailed monitoring using multiple, complementary detection methods. A fluorescein tracer test in the aquifer plus laboratory column data suggested that the very-aggressive flow conditions necessary to achieve 2.5 m of nZVI transport could be obtained using a hydraulically constrained flow path between injection and extraction wells. However, total unoxidized nZVI was transported only about 1 m and <2% of the injected nZVI concentration reached that distance. The experimental data also indicated that groundwater flow changed during injection, likely due to hydrogen bubble formation, which diverted the nZVI away from the targeted flow path. The leading edge of the iron plume became fully oxidized during transport. However, within the plume, oxidation of nZVI decreased in a fashion consistent with progressive depletion of aquifer "reductant demand". To directly quantify the extent of nZVI transport, a spectrophotometric method was developed, and the results indicated that deployment of unoxidized nZVI for groundwater remediation will likely be difficult.

Ultrasound-guided radiofrequency ablation in the management of interdigital (Morton's) neuroma.

OBJECTIVE: To identify the benefits of ultrasound-guided radiofrequency ablation of Morton's neuroma as an alternative to surgical excision. MATERIALS AND METHODS: We studied a consecutive cohort of surgical candidates for Morton's neurectomy who we referred, instead, for radiofrequency ablation (RFA). Under local anaesthetic, RFA was performed under ultrasound guidance, by a single radiologist. This out-patient procedure was repeated after 4 weeks if necessary. We followed patients for a minimum of 6 months to assess their change in visual analogue pain scores (VAS), symptom improvement, complications and progression to surgical excision. RESULTS: Thirty feet in 25 patients were studied. There were 4 men and 21 women with an average age of 55 years (range 33-73 years). All had tried previous methods of conservative management. Forty percent presented with 2nd space neuromas and 60% with 3rd space ones. The average number of treatment sessions was 1.6 (range 1-3, mode 1). Prior to treatment, all patients had pain on activity (VAS average: 6.0, range 3-9). Post-treatment there was a statistically significant reduction in pain scores (post-RFA VAS average: 1.7, range 0-8, p < 0.001). The average overall symptom improvement was 76%. There was one minor complication of temporary nerve irritation. Three neuromas (10%) have progressed to surgical excision; 1 patient has ongoing, unchanged pain with no obvious cause. At 6 months, 26 out of 30 feet had a satisfactory outcome. CONCLUSION: Ultrasound-guided RFA has successfully alleviated patients' symptoms of Morton's neuroma in >85% of cases. Only 10% have proceeded to surgical excision in the short term.

Xpert® MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how?

Xpert ® MTB/RIF offers new and important possibilities for the diagnosis of sputum smear-negative tuberculosis (TB) and/or rifampicin (RMP) resistance, and many are encouraging rapid and widespread implementation. This simple test can be implemented almost everywhere, and it provides results within a few hours. In low-income countries (LICs), however, its cost, environmental limitations (stable and regular electricity, adequate room temperature) and difficulties involved in supply and maintenance are major obstacles. While it may be suitable for major reference hospitals, operational research is needed to evaluate the test and its additional yield above high-quality smear microscopy and clinical algorithms before its use at the peripheral level. In the meantime, direct microscopy should remain the initial diagnostic test for TB suspects. In most LICs, the prevalence of RMP resistance among new TB patients is very low; an Xpert MTB/RIF result indicating RMP resistance will thus always need confirmation by another test. In a population at high risk of RMP resistance (> 15%), however, the positive predictive value for RMP resistance by Xpert MTB/RIF is high, and identification of RMP resistance is an excellent proxy for multidrug-resistant TB (MDR-TB). The assay should be widely used for this purpose if, and only if, excellent MDR-TB management is available, both for ethical reasons and to reduce the risk of extensively drug-resistant TB.

Reporter phage and breath tests: emerging phenotypic assays for diagnosing active tuberculosis, antibiotic resistance, and treatment efficacy.

The rapid and accurate diagnosis of active tuberculosis (TB) and its drug susceptibility remain a challenge. Phenotypic assays allow determination of antibiotic susceptibilities even if sequence data are not available or informative. We review 2 emerging diagnostic approaches, reporter phage and breath tests, both of which assay mycobacterial metabolism. The reporter phage signal, Green fluorescent protein (GFP) or ß-galactosidase, indicates transcription and translation inside the recipient bacilli and its attenuation by antibiotics. Different breath tests assay, (1) exhaled antigen 85, (2) mycobacterial urease activity, and (3) detection by trained rats of disease-specific odor in sputum, have also been developed. When compared with culture, reporter phage assays shorten the time for initial diagnosis of drug susceptibility by several days. Both reporter phage and breath tests have promise as early markers to determine the efficacy of treatment. While sputum often remains smear and Mycobacterium tuberculosis DNA positive early in the course of efficacious antituberculous treatment, we predict that both breath and phage tests will rapidly become negative. If this hypothesis proves correct, phage assays and breath tests could become important surrogate markers in early bactericidal activity (EBA) studies of new antibiotics.

Cumulative impact of GM herbicide-tolerant cropping on arable plants assessed through species-based and functional taxonomies.

BACKGROUND, AIM AND SCOPE: In a gradualist approach to the introduction of crop biotechnology, the findings of experimentation at one scale are used to predict the outcome of moving to a higher scale of deployment. Movement through scales had occurred for certain genetically modified herbicide-tolerant (GMHT) crops in the UK as far as large-scale field trials. However, the land area occupied by these trials was still <1% of the area occupied by the respective non-GM crops. Some means is needed to predict the direction and size of the effect of increasing the area of GMHT cropping on ecological variables such as the diversity among species and trophic interactions. Species-accumulation curves are examined here as a method of indicating regional-scale impacts on botanical diversity from multiple field experiments. MATERIALS AND METHODS: Data were used from experiments on the effect of (GMHT) crops and non-GM, or conventional, comparators in fields sown with four crop types (beet, maize, spring and winter oilseed rape) at a total of 250 sites in the UK between 2000 and 2003. Indices of biodiversity were measured in a split-field design comparing GMHT with the farmers' usual weed management. In the original analyses based on the means at site level, effects were detected on the mass of weeds in the three spring crops and the proportion of broadleaf and grass weeds in winter oilseed rape, but not on indices of plant species diversity. To explore the links between site means and total taxa, accumulation curves were constructed based on the number of plant species (a pool of around 250 species in total) and the number of plant functional types (24), inferred from the general life-history characteristics of a species. RESULTS: Species accumulation differed between GMHT and conventional treatments in direction and size, depending on the type of crop and its conventional management. Differences were mostly in the asymptote of the curve, indicative of the maximum number of species found in a treatment, rather than the steepness of the curve. In winter oilseed rape, 8% more species were accumulated in the GMHT treatment, mainly as a result of the encouragement of grass species by the herbicide when applied in the autumn. (Overall, GMHT winter oilseed rape had strong negative effects on both the food web and the potential weed burden by increasing the biomass of grasses and decreasing that of broadleaf weeds.) In maize, 33% more species-a substantial increase-were accumulated in the GMHT than in the conventional, consistent with the latter's highly suppressive weed management using triazine herbicides. In the spring oilseed rape and beet, fewer species (around 10%) were accumulated in the GMHT than the conventional. The GMHT treatments did not remove or add any functional (life history) types, however. Differences in species accumulation between treatments appeared to be caused by loss or gain of rarer species. The generality of this effect was confirmed by simulations of species accumulation in which the species complement at each of 50 sites was drawn from a regional pool and subjected to reducing treatment at each site. Shifts in the species-accumulation parameters, comparable to those measured, occurred only when a treatment removed the rarer species at each site. DISCUSSION: Species accumulation provided a set of simple curve-parameters that captured the net result of numerous local effects of treatments on plant species and, in some instances, the balance between grass and broadleaf types. The direction of effect was not the same in the four crops and depended on the severity of the conventional treatment and on complex interactions between season, herbicide and crop. The accumulation curves gave an indication of potential positive or negative consequences for regional species pools of replacing a conventional practice with GMHT weed management. In this and related studies, a range of indicators, through which diversity was assessed by both species and functional type, and at both site and regional scales, gave more insight into effects of GMHT treatment than provided by any one indicator. CONCLUSIONS: Species accumulation was shown to discriminate at the regional scale between agronomic treatments that had little effect on species number at the field scale. While a comprehensive assessment of GM cropping needs to include an examination of regional effects, as here, the costs of doing this in all instances would be prohibitive. Simulations of diversity-reducing treatments could provide a theoretical framework for predicting the likely regional effects from in-field plant dynamics. RECOMMENDATIONS AND PERSPECTIVES: Accumulation curves potentially offer a means of linking within-site effects to regional impacts on biodiversity resulting from any change in agricultural practice. To guide empirical measurement, there is a scope to apply a methodology such as individual-based modelling at the field scale to explore the links between agronomic treatments and the relative abundance of plant types. The framework needs to be validated in practice, using species-based and functional taxonomies, the latter defined by measured rather than inferred traits.

Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity.

Epidemiological studies have associated arsenic exposure with many types of human cancers. Arsenic has also been shown to act as a co-carcinogen even at low concentrations. However, the precise mechanism of its co-carcinogenic action is unknown. Recent studies indicate that arsenic can interfere with DNA-repair processes. Poly(ADP-ribose) polymerase (PARP)-1 is a zinc-finger DNA-repair protein, which can promptly sense DNA strand breaks and initiate DNA-repair pathways. In the present study, we tested the hypothesis that low concentrations of arsenic could inhibit PAPR-1 activity and so exacerbate levels of ultraviolet radiation (UVR)-induced DNA strand breaks. HaCat cells were treated with arsenite and/or UVR, and then DNA strand breaks were assessed by comet assay. Low concentrations of arsenite (

Outcome of excision of megarectum in children with anorectal malformation.

BACKGROUND/PURPOSE: Megarectum in association with anorectal malformation contributes to chronic constipation and fecal incontinence. Resection of megarectum in anorectal malformation improves bowel function, but neuropathy and poor sphincter quality may affect the outcome of fecal continence adversely. The aim of this study was to evaluate the benefits of resection of megarectum in anorectal malformation and to ascertain the impact of anal sphincter quality and neuropathy on the outcome. METHODS: We studied 62 children with intractable fecal incontinence after repair of anorectal malformation between January 1991 and January 2005. All patients were investigated with anorectal manometry and anal endosonography under ketamine anesthesia. On endosonography, an intact or scarred internal anal sphincter (IAS) was classified as good and a fragmented or absent IAS as poor. On manometry, a resting anal sphincter pressure equal to or more than 30 mm Hg was classified as good and a lower pressure as poor. Functional assessment of fecal continence was done before and after excision of megarectum using a modified Wingfield scores. RESULTS: Sixteen children had excision of megarectum with median age of 9 years (range, 2-15 years) and postoperative follow-up of 5 years (range, 1-10 years). Seven had formation of antegrade continent enema stoma before excision of megarectum. Children were classified into three groups of anomalies: low (n = 6), intermediate (n = 4), and high (n = 6). All children were incontinent of feces. After excision of megarectum, of the 9 children with good IAS and no neuropathy, 7 became continent of feces. Of the remaining 7 children, 4 had poor IAS and 3 had neuropathy, 5 of whom required an antegrade continent enema stoma to be clean. CONCLUSION: Excision of megarectum in children who had previous repair of anorectal malformation results in fecal continence in the presence of a good IAS and absence of neuropathy. Patients with a poor IAS or neuropathy will often require artificial means of fecal continence.

A midwife program of newborn resuscitation.

A very small proportion of newborns fail to establish a normal respiratory pattern without some assistance at birth and newborns requiring resuscitative measures at birth should have a skilled practitioner able to provide it. In this small hospital midwives felt unskilled in newborn resuscitation and paediatricians were not always immediately available. A stakeholder group gathered to discuss the problem. A training program was implemented that improved the skills, confidence and support of the attending midwife to resuscitate the newborn effectively. The aim was to improve the outcome for the infant whilst maintaining the mother's choice of birthing in a small local hospital close to family and friends.

Effects of lorazepam on fear-potentiated startle responses in man.

Sudden intense sensory stimuli elicit a cascade of involuntary responses, including a short-latency skeletal muscular response ('eyeblink startle response') and longer-latency autonomic responses. These responses are enhanced when subjects anticipate an aversive event compared to periods when subjects are resting ('fear potentiation'). It has been reported previously that the anxiolytic diazepam can suppress fear-potentiation of the eyeblink startle response in human volunteers. The present experiment aimed to confirm and extend these observations by examining the effect of another benzodiazepine, lorazepam, on the eyeblink and skin conductance components of the acoustic startle, and on fear-potentiation of these responses. Eighteen male volunteers participated in three weekly sessions in which they received oral treatment with placebo, lorazepam (1 mg) and lorazepam (2 mg), according to a balanced three-period, crossover, double-blind design. Two hours after ingestion of the treatments, electromyographic responses of the orbicularis oculi muscle and skin conductance responses were evoked by sound pulses during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with significant increase in the amplitude of the electromyographic (EMG) and skin conductance responses; there were also increases in baseline skin conductance, the number and amplitude of 'spontaneous' skin conductance fluctuations and self-rated anxiety. Lorazepam attenuated the effect of THREAT on self-rated anxiety and on the amplitude of the EMG response, but had no significant effect on fear-potentiation of the skin conductance responses. These results extend previous findings of the effect of diazepam on the fear-potentiated eyeblink startle response to lorazepam, and suggest that fear-potentiation of the later autonomic component of the startle response may be less sensitive to benzodiazepines than the fear-potentiated eyeblink response and self-rated anxiety.

Isosteric N-arylpiperazine replacements in a series of dihydropyridine NPY1 receptor antagonists.

4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1 receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones.

Effects of quetiapine and haloperidol on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (PPI). Here, we report the effects of the 'atypical' antipsychotic drug quetiapine and the 'conventional' antipsychotic haloperidol on these responses. Sixteen males (aged 19-38 years) participated in four sessions at 7-day intervals, in which they received quetiapine 12.5 mg, quetiapine 25 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 2 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage PPI was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Quetiapine 12.5 mg and 25 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses; haloperidol had no effect on EMG response amplitude or PPI. Neither drug affected N1/P2 amplitude or PPI of this response. Quetiapine, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not quetiapine, elevated serum prolactin level. The ability of quetiapine to attenuate the startle response may reflect its sedative action.