Pharmacokinetics and safety of repeated oral dosing of acetaminophen in adult horses.

BACKGROUND: There are no published studies on the pharmacokinetics of acetaminophen at the dosage used clinically (20 mg/kg), nor has the safety of multiple doses in horses been investigated. OBJECTIVE: Define the pharmacokinetic parameters of oral acetaminophen at 20 mg/kg in adult horses as a single dose, and twice daily for 14 days to assess the safety of multiple dosing. STUDY DESIGN: Pharmacokinetic study, multiple dose safety study. METHODS: Eight healthy Thoroughbred geldings were given acetaminophen (20 mg/kg; 500 mg tablets) orally as a single dose followed by doses every 12 h for 14 days. Serial blood samples were collected for determination of plasma acetaminophen concentrations using high performance liquid chromatography with ultraviolet detection. Serum biochemical analysis, gastroscopy and liver biopsy were examined during the safety study. RESULTS: Following a single dose, mean maximum concentration (Cmax ) was 16.61 µg/mL at 1.35 h (Tmax ), and drug concentration was below the lower limit of detection in most horses by 24 h. Elimination half-life (T1/2 ) was 2.78 h. No significant accumulation was noted following multiple doses. Average Cmax of acetaminophen following multiple oral dosing was 15.85 µg/mL, with a Tmax of 0.99 h and T1/2 of 4 h. Serum activities of sorbitol dehydrogenase were significantly decreased and total bilirubin concentrations were significantly increased following the last dose. No statistically significant changes were noted in gastroscopy scores. MAIN LIMITATIONS: Only one dose level (20 mg/kg) was studied, sample size was small and only a single breed and sex was used, with no pretreatment liver biopsies. CONCLUSION: This study described the pharmacokinetics of acetaminophen following single and multiple 20 mg/kg oral doses in adult horses and demonstrated the safety of acetaminophen with multiple oral dosing over 14 days. The summary is available in Portuguese - see Supporting information.

Rotation-dependent nonlinear absorption of orbital angular momentum beams in ruby.

We investigate the effect of a rotating medium on orbital angular momentum (OAM)-carrying beams by combining a weak probe beam shifted in frequency relative to a strong pump beam. We show how the rotational Doppler effect modifies the light-matter interaction through the external rotation of the medium. This interaction leads to an absorption that increases with the mechanical rotation velocity of the medium and with a rate that depends on the OAM of the light beam.

Pharmacokinetics of firocoxib after intravenous administration of multiple consecutive doses in neonatal foals.

The purpose of this study was to determine the pharmacokinetic profile of intravenous firocoxib in neonatal foals. Six healthy foals were administered 0.09 mg/kg firocoxib intravenously once a day for 7 days. Blood was collected for plasma firocoxib analysis using high-performance liquid chromatography with fluorescence detection at times 0 (day 1 of study only) and 0.08, 0.25, 1, 2, 4, 6, 8, 16 and 24 hr on dose numbers 1, 5 and 7. Blood was also collected immediately prior to doses 3, 4, 5 and 7. Final samples were collected at 36, 48, 72 and 96 hr following the final dose. Noncompartmental analysis using the trapezoidal method with linear interpolation revealed a moderate half-life (15.9 ± 9.1 hr) with a large volume of distribution at steady state (1.79 ± 0.57 L/kg) and a clearance (96.0 ± 59.2 ml h-1  kg-1 ) that was more rapid than that observed in adult horses.

Spine fracture prevalence in a nationally representative sample of US women and men aged ≥40 years: results from the National Health and Nutrition Examination Survey (NHANES) 2013-2014.

Spine fracture prevalence is similar in men and women, increasing from <5 % in those <60 to 11 % in those 70-79 and 18 % in those ≥80 years. Prevalence was higher with age, lower bone mineral density (BMD), and in those meeting criteria for spine imaging. Most subjects with spine fractures were unaware of them. INTRODUCTION: Spine fractures have substantial medical significance but are seldom recognized. This study collected contemporary nationally representative spine fracture prevalence data. METHODS: Cross-sectional analysis of 3330 US adults aged ≥40 years participating in NHANES 2013-2014 with evaluable Vertebral Fracture Assessment (VFA). VFA was graded by semiquantitative measurement. BMD and an osteoporosis questionnaire were collected. RESULTS: Overall spine fracture prevalence was 5.4 % and similar in men and women. Prevalence increased with age from <5 % in those <60 to 11 % in those 70-79 and 18 % in those ≥80 years. Fractures were more common in non-Hispanic whites and in people with lower body mass index and BMD. Among subjects with spine fracture, 26 % met BMD criteria for osteoporosis. Prevalence was higher in subjects who met National Osteoporosis Foundation (NOF) criteria for spine imaging (14 vs 4.7 %, P < 0.001). Only 8 % of people with a spine fracture diagnosed by VFA had a self-reported fracture, and among those who self-reported a spine fracture, only 21 % were diagnosed with fracture by VFA. CONCLUSION: Spine fracture prevalence is similar in women and men and increases with age and lower BMD, although most subjects with spine fracture do not meet BMD criteria for osteoporosis. Since most (>90 %) individuals were unaware of their spine fractures, lateral spine imaging is needed to identify these women and men. Spine fracture prevalence was threefold higher in individuals meeting NOF criteria for spine imaging (∼1 in 7 undergoing VFA). Identifying spine fractures as part of comprehensive risk assessment may improve clinical decision making.

Can intravenous conscious sedation with midazolam be effective at facilitating surgical dentistry in adolescent orthodontic patients? A service evaluation.

Background Surgical dentistry during orthodontic care often occurs in adolescence and may involve surgical removal or exposure of teeth. The invasive nature of treatment, combined with dental anxiety, means care can often be provided under general anaesthesia (GA). Best-practice guidelines however endorse conscious sedation as an alternative, where appropriate. Although a limited number of studies have shown safe and effective use of intravenous conscious sedation (IVCS) with midazolam in this cohort, robust evidence to support routine use is lacking. Aim To assess whether IVCS with midazolam can effectively facilitate surgical dentistry in adolescent orthodontic patients in primary care.Method A retrospective service evaluation was undertaken reviewing clinical records of adolescents (aged 12-15 years) undergoing surgical exposure and/or surgical removal of teeth under IVCS with midazolam.Results A total of 174 adolescents (mean age 14.2 years) attended for treatment between 2009 and 2015. Of these adolescents, 98.9% (N = 172) allowed cannulation, with all surgical dentistry completed during a single visit. Midazolam dose ranged from 2-7 mg with 79.1% of patients having good or excellent cooperation and three minor adverse events occurring.Conclusion This service evaluation shows IVCS with midazolam can effectively facilitate surgical orthodontics in carefully selected adolescents. There is however a distinct need to further explore potential for this technique to provide a viable alternative to GA.

A study of dental students' clinical knowledge acquisition and experiences in conscious sedation.

AIM: To evaluate final year dental students' knowledge acquisition and experiences during their intravenous sedation (IVS) clinical attachment within the sedation department at Newcastle School of Dental Sciences (NSDS). METHODS: Students attending IVS clinical attachments in the period September 2012 - April 2013 completed a novel clinical knowledge test at the beginning and end of their one week attachment; a feedback questionnaire was also completed. RESULTS: A total of 70 students attended the attachment. Clinical knowledge tests were completed by 71.4% (n = 50) of students. The average test result improved from 75.1% in the pre-attachment test to 92.1% in the post-attachment test. Feedback questionnaires were returned by 65.7% (n = 46) of students. All students attained clinical experience of administering sedation and treating sedated patients. 'Teaching and Clinical Support' was rated highest, with 97.8% (n = 45) rating it as excellent. Students commented that hands-on clinical experience and clinical teaching were the most valuable parts of the attachment. Patients failing to attend appointments were considered the least useful part of the attachment. CONCLUSION: This pilot study provides an insight into undergraduate clinical sedation, which is often under reported in the literature. The clinical experience gained at NSDS exceeds GDC recommendations for undergraduate sedation. The clinical knowledge test results suggest that clinical knowledge may be better retained after direct clinical experience.

Escorts' knowledge of their duty of care to patients who have undergone intravenous sedation.

AIM: To assess escorts' understanding of their responsibilities to the patient 24 hours following dental treatment under intravenous sedation. STANDARDS: One hundred per cent of escorts: have been informed of their duties, have read the information sheet, expect at least a one hour appointment, identify the hazardous activities patients should avoid following sedation, travel by private transport, are aware that medications are taken as normal, should have care in place 24 hours following sedation. METHOD: This was a prospective questionnaire-based audit. Questionnaires were handed to escorts of patients receiving treatment under intravenous sedation in Newcastle Dental Hospital sedation department. RESULTS: Of 104 responses, 91.3% of escorts were informed about their duties and 79.8% had read the information sheet prior to the appointment. Boiling a kettle and Internet use were the most selected hazardous activities that escorts deemed safe for patients to carry out postoperatively (19.2%, 23.0%.) Private transport home was mainly used (car 73.1%, taxi 24.9%.) Following sedation, 93.3% of patients had an escort for 24 hours. CONCLUSION: Escorts' basic knowledge fell short of the standard. Improvements are needed to ensure patient safety. RECOMMENDATIONS: At the pre-assessment, the patient might be given an information sheet solely for the escort and encouraged to explain this to the escort. More comprehensive information listing activities hazardous to the patient 24 hours following sedation and emphasising that taking medications as normal preoperatively could be available on the treatment day. Transport information in the appointment letter might improve access. A Trust website link, a DVD and posters in the waiting room could further inform.

PTPN14 interacts with and negatively regulates the oncogenic function of YAP.

The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition and malignant transformation. Here, we report a novel regulatory mechanism for the YAP oncogenic function via direct interaction with non-receptor tyrosine phosphatase 14 (PTPN14) through the WW domain of YAP and the PPxY domain of PTPN14. We also found that YAP is a direct substrate of PTPN14. In addition, luciferase reporter assay showed that the inhibition of the YAP transcriptional co-activator function by PTPN14 is mediated through their protein interactions and may result from an increase in the inactive cytoplasmic form of YAP. Last, knockdown of PTPN14 induces the nuclear retention of YAP and increases the YAP-dependent cell migration. In summary, our results indicate a potential regulatory role of PTPN14 on YAP and demonstrate a novel mechanism in YAP regulation.

Oral urgent treatment (OUT) - a volunteer led training programme in North West Tanzania.

Oral health is recognised as a fundamental contributor to general health. In many developing countries resources are scarce and access to oral healthcare is often limited, particularly in rural areas. An approach to solving the problem of providing oral healthcare in developing nations is the Basic Package of Oral Care (BPOC), which promotes the community-oriented promotion of oral health and affordable and effective interventions. The aim of this paper is to focus on one component of the BPOC, by presenting a model for the provision of a local training programme of oral urgent treatment (OUT), delivered by volunteers, in a region of North West Tanzania.

An in vivo comparison of hip structure analysis (HSA) with measurements obtained by QCT.

SUMMARY: In a population of elderly women, bone cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), femoral neck axis length (FNAL), and width measured with hip structure analysis (HSA) on dual-energy x-ray absorptiometry (DXA) images in the femoral neck and trochanteric regions are highly correlated to quantitative computed tomography (QCT) measurements. INTRODUCTION: HSA is a method of obtaining measurements of proximal femur structure using 2D DXA technology. This study was designed to examine the correlations between HSA measurements and 3D QCT. METHODS: Forty-one women (mean age, 82.8 ± 2.5 years) were measured using DXA and a 64-slice CT scanner (1 mm slice thickness, 0.29 mm in plane resolution). HSA parameters were calculated at the narrow neck (NN) and trochanteric (IT) regions on the DXA image. These regions were then translated to anatomically equivalent regions on the QCT dataset by co-registering the DXA image and QCT dataset using four DXA images acquired at different angles. RESULTS: At the NN and IT regions, high linear correlations were measured between HSA and QCT for CSA r = 0.95 and 0.93, CSMI r = 0.94 and 0.93, and Z r = 0.93 and 0.89, respectively. All correlations were highly significant (p < 0.001), but there were differences in slope and offset between the two techniques, at least in part due to differences in calibration between the two techniques. FNAL and width of the bone at the NN and IT regions, physical measurements independent of the calibration, were highly correlated (r = 0.90-0.95, p < 0.001) and had slopes close to 1.0 (range, 0.978 to 1.003). CONCLUSION: CSA, CSMI, Z, FNAL, and width measured by HSA correlate highly to high-resolution QCT.

Differences in structural geometrical outcomes at the neck of the proximal femur using two-dimensional DXA-derived projection (APEX) and three-dimensional QCT-derived (BIT QCT) techniques.

UNLABELLED: Structural geometric parameters at neck of the proximal femur were obtained using DXA-derived hip structural analysis (APEX 3) and quantitative computed tomography-derived (BIT QCT) techniques in 237 elderly females. Linear correlations for parameters ranged from 0.45 to 0.90. The average value of the subperiosteal width, as determined by the two techniques, was the same; variables dependent on mass measurements were different. INTRODUCTION: There has been increasing interest in using bone structural geometry to assess bone fragility to complement bone mineral mass. The objective of this study is to compare structural geometrical differences between "2D" DXA-derived and "3D" QCT-derived techniques in unselected clinical cases. METHODS: All 237 females had both DXA and QCT assessments of femoral neck structural geometry. Variables compared were areal bone mineral density, cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), averaged cortical thickness (Ct), endosteal width (ESW), subperiosteal width (W), and buckling ratio (BR). RESULTS: Correlation of femoral neck variables ranged from 0.45 for ESW to 0.90 for CSA. APEX 3 and BIT QCT-derived femoral neck W values were numerically similar. However CSA, CSMI, Z and Ct values measured by APEX 3 were higher and ESW and BR values were lower than corresponding BIT QCT. CONCLUSIONS: 2D DXA structural analysis of neck of femur is related to but different from same parameters calculated from true 3D images obtained by CT. Femoral neck size values are similar for DXA and QCT, but structural geometrical variables dependent on mass calibration standards, location of neck ROI and mathematical derivation techniques are different.

(S)-Lysine adsorption induces the formation of gold nanofingers on Au{111}.

STM imaging following the adsorption of (S)-lysine on Au{111} leads to the observation of Au nanofingers whose growth directions correlate with the unit cell vectors of ordered 2-D phases of lysine. The likely mechanism of surface restructuring is discussed.

Anxiety and quality of life in phobic dental patients.

Little is known about the anxiety patients experience before attending for dental treatment. The aim of this study was to determine, in dentally phobic patients, the temporal relationship of pre-operative anxiety levels, and the disruption to daily life caused by this. Twenty-four phobic and 19 comparison (non-phobic) dental patients were recruited. Four validated questionnaires were used to assess anxiety and quality of life, which each patient completed for 5 days prior to, and on the day of, treatment. Those in the experimental group were found to have significantly greater levels of dental and general anxiety, and a significantly lower quality of life compared with those in the comparison group. Significant temporal relationships were found with all of the questionnaires. Dental and general anxiety scores were significantly correlated with quality-of-life measures. This study suggests that phobic dental patients are experiencing significant increased anxiety, and significant negative quality-of-life effects, in this period.

Comparison of transmucosal midazolam with inhalation sedation for dental extractions in children. A randomized, cross-over, clinical trial.

BACKGROUND: The transmucosal route for conscious sedation in children has been reported widely in the field of medicine, but less so in dental patients. The aim of this study was to evaluate the efficacy and safety profile of midazolam (0.2 mg/kg) administered by the buccal transmucosal route, in comparison with nitrous oxide/oxygen inhalation sedation, for orthodontic extractions in 10-16-year-old dental patients. METHODS: Each patient attended for two visits and was randomly allocated to receive buccal midazolam (0.2 mg/kg) or nitrous oxide/oxygen titrated to 30%/70% at the first visit, the alternative being used at the second visit. The patients' vital signs, sedation levels and behavioural scores were recorded throughout. Post-operatively, side-effects, recall of the visit and satisfaction levels were recorded via questionnaire. RESULTS: Thirty-six patients, with a mean age of 12.9 years, completed both arms of the trial. The maximum level of sedation was achieved with buccal midazolam in a mean time of 14.42 min, compared with 7.05 min with inhalation sedation. The vital signs with both types of sedation remained within acceptable limits and the reported side-effects were of no clinical significance. Buccal midazolam was found to be acceptable by 65.7%. Only 28.6% of cases preferred this technique, the main disadvantage being the taste of the solution. CONCLUSION: Buccal midazolam sedation (0.2 mg/kg) seems to be equally as safe and effective as nitrous oxide/oxygen for the extraction of premolar teeth in anxious children. However, further research is required to refine the midazolam vehicle to improve acceptability.

A comparison of oral midazolam and nitrous oxide sedation for dental extractions in children.

The aim of the study was to compare oral midazolam and inhaled nitrous oxide as sedative agents during the management of children aged 5-10 years presenting for extraction of primary teeth under local anaesthetic. Subjects required two visits for the extraction of four primary teeth, one in each quadrant of the mouth, and were randomly allocated to be given nitrous oxide 30% in oxygen or oral midazolam 0.3 mg.kg(-1) at the first visit, the other technique being used at the second visit. Vital signs, sedation levels and behavioural scores were recorded, and postoperative recall and satisfaction were reported by the patients. Thirty-five children, with a mean [range] age of 7.4 [5-10] years, completed the treatment. The mean dose of oral midazolam given was 8.6 [3.3-16.5] mg. The mean times taken to achieve the maximum level of sedation for midazolam and nitrous oxide sedation were 15.9 [2-30] min and 6.8 [2-10] min, respectively. Physiological parameters remained within acceptable clinical limits for both types of sedation. Oral midazolam was considered acceptable by 59% and was preferred by 36%. Oral midazolam sedation in 5 to 10-year-old children was shown to be as safe and effective as nitrous oxide in oxygen sedation for extraction of primary teeth but would not be the method of choice for all patients.

High throughput approaches in neuroscience.

Traditional approaches to understanding biological problems are now being advanced with the use of high throughput technologies, which analyse multiple samples simultaneously, or thousands of analytes in a single sample. The application of these technologies in neurochemistry and neuroscience is beginning to be explored and is assisting in the development of new models of drug action, neuroanatomical investigations, and in identifying molecular pathways involved in neurological and psychiatric disease. Tools such as microarray-based gene expression profiling and 2D and multidimensional proteomic methods are uncovering functional components to a wide variety of neuroscience paradigms and the application of these technologies is set to become standard in analysis.

SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies.

The authors recently have shown that triplication of the alpha-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease.

Functional genomics and proteomics: application in neurosciences.

The sequencing of the complete genome for many organisms, including man, has opened the door to the systematic understanding of how complex structures such as the brain integrate and function, not only in health but also in disease. This blueprint, however, means that the piecemeal analysis regimes of the past are being rapidly superseded by new methods that analyse not just tens of genes or proteins at any one time, but thousands, if not the entire repertoire of a cell population or tissue under investigation. Using the most appropriate method of analysis to maximise the available data therefore becomes vital if a complete picture is to be obtained of how a system or individual cell is affected by a treatment or disease. This review examines what methods are currently available for the large scale analysis of gene and protein expression, and what are their limitations.

A survey of the opinions of consultant anaesthetists in Scotland of sedation carried out by dentists.

OBJECTIVES: To elicit the attitudes and opinions of consultant anaesthetists working in Scotland, with regard to conscious sedation carried out by dental practitioners. METHOD: A questionnaire was designed to gauge opinion of consultant anaesthetists in Scotland on the practice of conscious sedation by dentists. The questionnaire was sent to 353 consultant anaesthetists working in 49 hospitals within the 15 health boards in Scotland. RESULTS: Of the 366 questionnaires sent, 249 were returned of which 235 were valid. This gave a response rate of 64%. In general, those questioned felt that the provision of sedation in a hospital setting was more appropriate than in general dental practice. A majority (65%) thought that it was unrealistic for anaesthetists to provide all sedation for dental treatment, although many (58%) felt that anaesthetists should take more responsibility in this area. Again, a majority (60%) agreed that dentists should be trained to use sedation techniques for their patients but a significant number (63%) disagreed with the practice of operator/sedationist. CONCLUSION: It is of concern to the dental profession that a significant number of anaesthetists do not feel that it is appropriate for dentists to be administering even the most simple methods of sedation. At present there are no clear, recognised guidelines as to the level of formal training required for the practice of conscious sedation by dentists. It is in the interests of the dental profession and the public to ensure that those choosing to practice sedation do so safely by following recognised guidelines in the training and practice of sedation.

Randomized, controlled, cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing dental extractions.

BACKGROUND: The use of benzodiazepines for paediatric dental sedation has received limited attention with regard to research into clinical effectiveness. A study was therefore designed to investigate the use of midazolam, for i.v. sedation in paediatric dental patients. METHOD: The aim of the study was to assess the effectiveness of i.v. midazolam in a randomized, controlled, cross-over trial. Children aged 12-16 yr (ASA I and II), requiring two appointments for equivalent but contralateral dental extractions for orthodontic purposes, were recruited. Conscious sedation with either i.v. midazolam titrated at 0.5 mg x min(-1), to a maximum of 5 mg, or nitrous oxide/oxygen titrated to 30%/70% inhalation sedation was used at the first visit, the alternative being used at the second visit. Vital signs including blood pressure, arterial oxygen saturation and ventilatory frequency, as well as sedation levels and behavioural scores, were recorded every 2 min. RESULTS: Forty patients, mean age 13.2 yr (range 12-16 yr), participated in the trial. A mean dose of midazolam 2.8 mg was administered in the test group. The median time to the maximum level of sedation was 8 min for midazolam compared with 6 min for nitrous oxide (P<0.001). Vital signs for both treatments were comparable and within acceptable clinical limits and communication with the patient was maintained at all times. The median (range) lowest arterial oxygen saturation level recorded for midazolam was 97 (91-99)% compared with 97 (92-100)% for nitrous oxide. The mean (range) recovery time for midazolam was 51.6 (39-65) min and 23.3 (20-34) min for nitrous oxide (P<0.0001). Fifty-one per cent said they preferred i.v. midazolam, 38% preferred nitrous oxide, and 11% had no preference. CONCLUSION: I.V. midazolam sedation (0.5 mg x min(-1) to a maximum of 5 mg) appears to be as effective as nitrous oxide sedation in 12-16-yr-old healthy paediatric dental patients.