Behavioral, metabolic, and lipidomic characterization of the 5xFADxTg30 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with both extracellular amyloid-ß (Aß) plaques and intracellular tau-containing neurofibrillary tangles (NFT). We characterized the behavioral, metabolic and lipidomic phenotype of the 5xFADxTg30 mouse model which contains overexpression of both Aß and tau. Our results independently reproduce several phenotypic traits described previously for this model, while providing additional characterization. This model develops many aspects associated with AD including frailty, decreased survival, initiation of aspects of cognitive decline and alterations to specific lipid classes and molecular lipid species in the plasma and brain. Notably, some sex-specific differences exist in this model and motor impairment with aging in this model does compromise the utility of the model for some movement-based behavioral assessments of cognitive function. These findings provide a reference for individuals interested in using this model to understand the pathology associated with elevated Aß and tau or for testing potential therapeutics for the treatment of AD.

Clinical outcomes among patients with tuberculous meningitis receiving intensified treatment regimens.

SETTING: National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.OBJECTIVE: To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.DESIGN: Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.RESULTS: Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.CONCLUSION: Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.

Highly Variable Expression of ESR1 Splice Variants in Human Liver: Implication in the Liver Gene Expression Regulation and Inter-Person Variability in Drug Metabolism and Liver Related Diseases.

Estrogen receptor alpha (ESR1) plays an important role in many tissues including the liver. Numerous alternative splice variants of ESR1 exist that encode ESR1 proteins with varying functions. We aim to study ESR1 genomic organization and its mRNA expression profile in human liver by incorporating information from literature and genomic databases (Ensembl, NCBI and GTEx), and employing a quantitative method to measure all known ESR1 mRNA splice variants in 36 human livers. We re-constructed ESR1 genomic organization map that contains 29 exons. ESR1 mRNA splice variants with varying 5' untranslated region (5'UTR) and/or missing each of eight coding exons are readily detectable in liver and other tissues. Moreover, we found extensive inter-individual variability in splice variant pattern of ESR1 transcripts. Specifically, ESR1 transcripts lacking first coding exon are the main transcripts in liver, which encode ESR1 proteins missing N-terminal 173 amino acids (for example, ERα46), reported previously to have either constitutive activity or dominant negative effects depending on cellular context. Moreover, some livers predominantly express ESR1 transcripts missing exon 10 or 16, encoding C-terminal truncated ESR1 proteins with varying ESR1 activities. Inter-person variability in ESR1 expression profile may contribute to inter-person variability in drug metabolism and susceptibility to liver related diseases.

Prevalence of pulmonary tuberculosis among students in three eastern Ethiopian universities.

SETTINGS: Three universities located in eastern Ethiopia: Haramaya University, Haramaya; Dire-Dawa University, Dire-Dawa; and Jigjiga University, Jigjiga. OBJECTIVE: To determine the burden of pulmonary tuberculosis (PTB) among university students and to identify risk factors for the development of TB disease. DESIGN: All full-time university students were screened for symptoms of PTB and sputum was collected for acid-fast bacilli (AFB) examination and culture for Mycobacterium tuberculosis. RESULTS: Of 35 344 students screened, we identified 153 PTB cases that occurred over the 1-year study period, or 433/100 000 students. Of these, 117 (76%) PTB cases were found through passive case finding at student health centres, while 36 (24%) previously undiagnosed patients were identified through active case finding. Sixteen cases detected using active case finding (44%) were smear-positive. Living in a dormitory with 5 students and attending university for 2 years were both significantly associated with PTB (adjusted OR 2.49 and 3.79, respectively, P < 0.001). In persons who underwent drug susceptibility testing, 11 (30.5%) had resistance to at least one first-line anti-tuberculosis drug. CONCLUSION: We found a high burden of TB among university students in eastern Ethiopia. Screening for PTB upon university admission and at regular intervals should be considered to minimise TB transmission on university campuses.

The interdisciplinary management of hypodontia patients in the UK: a national service evaluation.

Objective To examine the distribution of interdisciplinary clinics for hypodontia patients in the UK and to assess the provision of orthodontic-restorative care for hypodontia patients in units where this service is and is not available.Design Prospective, online-questionnaire.Setting Hospital orthodontic departments in the UK.Participants In total, consultants from 92 orthodontic departments completed the questionnaire.Methods Orthodontic consultants were asked to complete a questionnaire regarding the provision of orthodontic-restorative care for hypodontia patients in their units.Results Overall, 100% of teaching hospitals and 51% of district general hospitals (DGHs) that responded have an interdisciplinary clinic for hypodontia patients. In 51% of units, the majority of patients assessed on the interdisciplinary clinic undergo their restorative care at the same secondary care unit. In 59% of units where an interdisciplinary clinic is not available most of the restorative care for hypodontia patients is provided by the GDP, whilst in 38% of units a specialist restorative dentist in another secondary care unit provides most of the restorative care.Conclusions The provision of an interdisciplinary clinic for hypodontia patients varies amongst hospital units throughout the UK. The provision of orthodontic-restorative care for hypodontia patients also varies between these units.

Utility of 18F-fluoroestradiol (18F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy.

BACKGROUND: Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. 18F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes 18F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. METHODS: Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with 18F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with 18F-FES 1-5 days post administration of Z-endoxifen. RESULTS: Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. CONCLUSION: F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

The role of the general dental practitioner in managing patients who self-harm.

There has been a reported increase in the incidence of self-harm within the United Kingdom. This is of great concern, as a number of studies have shown self-harm to be a major risk factor to completed suicide. However, the identification of self-harm provides an opportunity for support and treatment. Mental health is an area that often receives little attention in the undergraduate dental curriculum. Yet dental practitioners, as healthcare professionals, need to be vigilant for any risk factors or signs of mental illness among their patients and make appropriate onward referrals. The purpose of this article is to examine the current evidence and aspects of self-harm, particularly in young adults and adolescents that are relevant within a dental settling.

Merrill Jon Egorin, MD, 1948-2010.

Merrill Egorin was born in Baltimore, Maryland, where he completed his undergraduate and graduate education. He was a pioneer in understanding the relationship of pharmacokinetic variability to the pharmacodynamics of anticancer agents. He is remembered as a compassionate physician, an outstanding scientist, an entertaining lecturer, a superb mentor, and a friend to many.

A national study of cross infection control: 'are we clean enough?'.

OBJECTIVE: To establish what cross infection control policies and procedures are in place within UK orthodontic departments and how they compare with recommended guidelines. DESIGN: A hospital-based cross-sectional study investigating UK orthodontic departments between March 2007 and January 2008. SUBJECTS AND METHODS: The main outcome measure was a questionnaire constructed for the study, based on current cross infection control guidelines. All orthodontic departments within district general hospitals were invited to participate via email and the response rate was 48%. RESULTS: Five key areas were explored, which included a) training, education and personal protection, b) the clinical environment, c) decontamination of instruments, d) decontamination of appliances and impressions and e) disposal of waste. Ninety-eight percent of departments provided training in cross infection control and 98% also had a policy to check staff immunisation status. With respect to the clinical environment, 97% of the departments surveyed had separate 'clean' and 'dirty' zones. Half of all departments used central sterile services departments (CSSD) for instrument sterilisation. Seventy-eight percent of departments had a policy to decontaminate impressions/appliances at the chairside and all departments used 'yellow bags' for clinical waste and puncture-proof containers for sharps waste. CONCLUSIONS: UK orthodontic departments have implemented policies and procedures which would ensure a high standard of cross infection control. In particular, this related to the decontamination of surfaces and instruments, the use of personal protection and disposal of clinical waste. Most departments had policies and procedures in place for staff education and training in cross infection control and personal protection.

Factors which influence working patterns of orthodontists in the United Kingdom.

OBJECTIVE: To describe factors which influence the current working patterns of orthodontists in the United Kingdom. DESIGN AND SETTING: A cross-sectional postal questionnaire to orthodontic specialists in the United Kingdom. SUBJECTS: All those on the specialist list in orthodontics held by the General Dental Council in 2006-2007. MATERIALS AND METHODS: The data gathered included demographic details (gender, ethnicity, age, professional status and number of children), calendar year of achieving professional qualifications and current working patterns, together with details of any career breaks taken and geographical location of work. RESULTS: The response rate was 81.5%. Male and female orthodontists were seen to have different working patterns. The difference was statistically significant with male orthodontists undertaking clinical work on average 1.5 sessions more per week than their female colleagues. The calendar year of completion of undergraduate studies and the number of children an orthodontist has can significantly affect the number of clinical sessions they work each week. In recent years it has been observed that there is greater ethnic diversity among the workforce but ethnic origin appeared to have a minimal effect on the number of clinical sessions worked each week. The amount and length of career breaks taken by female orthodontists was greater than their male colleagues. In addition, there continues to be an uneven distribution of orthodontists throughout the United Kingdom. CONCLUSION: Many factors influence the current working patterns of orthodontists in the United Kingdom. However, it may be the inequitable regional distribution of orthodontists throughout the United Kingdom which is of greatest significance to orthodontic workforce planning for the future.

Changes in the gender and ethnic balance of the United Kingdom orthodontic workforce.

OBJECTIVE: To describe the gender and ethnic trends of the United Kingdom orthodontic workforce. DESIGN AND SETTING: A cross-sectional survey using a postal questionnaire to specialist orthodontic practitioners in the United Kingdom (2006-2007).Subjects All those on the Specialist List in Orthodontics held by the General Dental Council in October 2006. MATERIALS AND METHODS: The data collected using the questionnaire included demographic details (gender, ethnicity, current age, place of birth), undergraduate and postgraduate dental schools attended, calendar years in which professional qualifications were achieved, anticipated year of retirement and geographical location of work place. RESULTS: The response rate was 81.5%. There are more male (60.2%) than female (39.8%) orthodontists presently working in the United Kingdom. Minority ethnic groups are better represented amongst the orthodontic workforce than they are in the general population, however their distribution throughout the United Kingdom is uneven. The trends in the results indicate that the gender and ethnic balance of the specialist orthodontic workforce has been changing and the proportion of females and those from non-white ethnic groups has increased. In contrast, the majority of those retiring over the next few years will be white males (60%). CONCLUSION: This study suggests that there will be greater ethnic diversity and more female orthodontists in the future workforce. Consequently, working patterns should be kept under regular review so that an optimal orthodontic service can be maintained in the United Kingdom.

Contribution of indirect computed tomography venography to computed tomography angiography of the chest for the diagnosis of thromboembolic disease in two United States emergency departments.

Recent reports suggest that physicians in non-ambulatory settings can use indirect CT venography (CTV) of the lower extremities immediately following spiral CT angiography (CTA) of the chest to identify patients with a negative CTA who have thromboembolic disease identified on CTV. We sought to determine the frequency of isolated deep venous thrombosis (DVT) discovered on CTV in emergency department (ED) patients with complaints suggestive of pulmonary embolism (PE) yet having a negative CTA. This study was conducted in a suburban and urban ED where patients with symptoms suspicious for PE were primarily evaluated with CTA and CTV. A total of 800 patients were studied, including 360 from the suburban ED and 440 from the urban ED. 88 (11%) patients were diagnosed with thromboembolic disease by CTA, or CTV, or both. Seventy-three patients had a CTA of the chest that was positive for PE, 42 (5.2%) of whom had evidence of both PE on CTA and DVT on CTV. Fifteen patients (2%, 95% CI = 1-3%) had a negative CTA and were subsequently found to have isolated DVT on CTV, all of whom received anticoagulation therapy. These data suggest that indirect CT venography of immediately following CT angiography of the chest significantly increased the frequency of diagnosed thromboembolic disease requiring anticoagulation in ED patients with suspected PE.

Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes.

Vanoxerine (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; GBR12909) is a promising agent for the treatment of cocaine dependence. Knowledge of the major pathway for GBR12909 metabolism is important for prediction of the likelihood of drug-drug interactions, which may affect the therapeutic clinical outcome, when this agent is used in cocaine-dependent individuals receiving multiple drug therapy. We studied biotransformation of GBR12909 in human liver microsomes (n = 4), human hepatocytes, and microsomes containing cDNA-expressed human P450 isoforms with GBR12909 concentrations within the range of steady-state plasma concentrations detected in healthy volunteers. A high-pressure liquid chromatography assay was used to measure parent GBR12909 and its primary metabolite. GBR12909 was metabolized by human liver microsomes, hepatocytes, and cDNA-expressed human P450s to a single metabolite. Ketoconazole, a selective inhibitor of CYP3A, reduced GBR12909 biotransformation in human liver microsomes and primary hepatocytes by 92 +/- 2 and 92.4 +/- 0.4%, respectively. Quercetin (an inhibitor of CYP2C8/3A4) was a less effective inhibitor producing 62 +/- 22% inhibition in human liver microsomes and 54 +/- 35% in hepatocytes. Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 +/- 18.5% in primary human hepatocytes. Ciprofloxacin (CYP1A2), sulfaphenazole (CYP2C9), quinidine (CYP2D6), chlorzoxazone (CYP2E1), and mephenytoin (CYP2C19) did not demonstrate statistically significant inhibition (p > 0.05) of GBR12909 biotransformation in liver microsomes. cDNA-expressed P450 3A4 metabolized GBR12909 to a greater extent than 2C8 and 2E1. These data suggest the possibility that multiple P450 isoforms may be involved in human GBR12909 metabolism but that CYP3A appears to be the major enzyme responsible for human GBR12909 biotransformation.

Inter-species differences in drug properties.

There has been a clear trend towards decreased reliance upon animal studies and increased emphasis upon experiments with human-derived tissues. Nonetheless, we continue to need investigations of interspecies differences for two principal reasons: (1) to prospectively design experiments so that the animal species most similar to humans can be chosen, on a case-by-case basis, for each drug; (2) to properly evaluate and interpret data obtained from the experiments ("risk assessment"). Four core examples derived from the work in our FDA laboratory are used to illustrate these points. For paclitaxel, different metabolites were formed in humans and rats, which makes metabolic drug-drug interaction studies in rats irrelevant. For zidovudine (AZT), rapid glucuronidation in humans produced a much shorter half-life than expected from studies in animals, which have negligible glucuronidation. The toxicology and efficacy of both parent drug and metabolite need to be assessed in cases such as iododeoxydoxorubicin, in which the parent molecule is the dominant circulating species in mice, but patients have more than 10-fold greater exposure to the metabolite compared with the parent. While rats have highly-active arylamine N-acetyltransferases, dogs totally lack this enzyme family, and humans have intermediate amounts. For some situations, we've suggested that it can be desirable to inhibit NAT to make the human exposure more similar to dogs. In conclusion, although the ratio of animal:human data is decreasing, our ability to use animal data effectively for drug development has actually increased. Continued focus should be placed upon the application of comparative interspecies data for prospective design of animal experiments and retrospective interpretation of animal findings in terms of the potential for human risk and benefit.