Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models.

Aggregated tau protein is a core pathology present in several neurodegenerative diseases. Therefore, the development and application of positron emission tomography (PET) imaging radiotracers that selectively bind to aggregated tau in fibril form is of importance in furthering the understanding of these disorders. While radiotracers used in human PET studies offer invaluable insight, radiotracers that are also capable of visualizing tau fibrils in animal models are important tools for translational research into these diseases. Herein, we report the synthesis and characterization of a novel library of compounds based on the phenyl/pyridinylbutadienylbenzothiazoles/benzothiazolium (PBB3) backbone developed for this application. From this library, we selected the compound LM229, which binds to recombinant tau fibrils with high affinity (Kd = 3.6 nM) and detects with high specificity (a) pathological 4R tau aggregates in living cultured neurons and mouse brain sections from transgenic human P301S tau mice, (b) truncated human 151-351 3R (SHR24) and 4R (SHR72) tau aggregates in transgenic rat brain sections, and (c) tau neurofibrillary tangles in brain sections from Alzheimer's disease (3R/4R tau) and progressive supranuclear palsy (4R tau). With LM229 also shown to cross the blood-brain barrier in vivo and its effective radiolabeling with the radioisotope carbon-11, we have established a novel platform for PET translational studies using rodent transgenic tau models.

Trends in and predictors of pregnancy termination among 15-24 year-old women in Nigeria: a multi-level analysis of demographic and health surveys 2003-2018.

BACKGROUND: Three-quarters of pregnancy terminations in Africa are carried out in unsafe conditions. Unsafe abortion is the leading cause of maternal mortality among 15-24 year-old women in Sub-Saharan Africa. Greater understanding of the wider determinants of pregnancy termination in 15-24 year-olds could inform the design and development of interventions to mitigate the harm. Previous research has described the trends in and factors associated with termination of pregnancy for women of reproductive age in Nigeria. However, the wider determinants of pregnancy termination have not been ascertained, and data for all women have been aggregated which may obscure differences by age groups. Therefore, we examined the trends in and individual and contextual-level predictors of pregnancy termination among 15-24 year-old women in Nigeria. METHODS: We analysed data from the 2003, 2008, 2013 and 2018 Nigerian Demographic and Health Surveys (NDHS) comprising 45,793 women aged 15-24 years. Trends in pregnancy termination across the four survey datasets were examined using bivariate analysis. Individual and contextual predictors of pregnancy termination were analysed using a three-level binary logistic regression analysis and are reported as adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: Trends in pregnancy termination declined from 5.8% in 2003 to 4.2% in 2013 then reversed to 4.9% in 2018. The declining trend was greater for 15-24 year-old women with higher socioeconomic status. Around 17% of the total variation in pregnancy termination was attributable to community factors, and 7% to state-level factors. Of all contextual variables considered, only contraceptive prevalence (proxy for reproductive health service access by young women) at community level was significant. Living in communities with higher contraceptive prevalence increased odds of termination compared with communities with lower contraceptive prevalence (aOR = 4.2; 95% CI 2.7-6.6). At the individual-level, sexual activity before age 15 increased odds of termination (aOR = 2.3; 95% CI 1.9-2.8) compared with women who initiated sexual activity at age 18 years or older, and married women had increased odds compared with never married women (aOR = 3.0; 95% CI 2.5-3.7). CONCLUSION: Our findings highlight the importance of disaggregating data for women across the reproductive lifecourse, and indicates where tailored interventions could be targeted to address factors associated with pregnancy termination among young women in Nigeria.

The European burden of primary varicose veins.

BACKGROUND: The treatment of varicose veins has been demonstrated to improve quality of life, alleviate symptoms of depression and treat the complications of venous disease. This study aims to show the studies which contain information regarding the prevalence and distribution of venous disease. Then using the population and prevalence data for venous disease, and considering the cost of treating varicose veins, this study aims to analyse the treatment of varicose veins and assess whether there is a disparity between European countries. METHODS: Relevant papers regarding the prevalence or incidence of venous disease were identified through searches of PubMed (1966 to October 2010). The search terms 'prevalence OR incidence' AND 'varicose veins or venous disease' were used. Population data, prevalence data and the number of varicose vein procedures performed in each country was obtained for 2010. RESULTS: Four studies were included. From calculated values comparing the predicted and actual number of patients requiring treatment for venous disease, the UK, Finland and Sweden are potentially not treating all patients with C2 disease. In contrast to this, all other European countries represented are treating more patients, suggesting that they may be treating additional patients. There was up to a four-fold difference in the numbers of procedures per million population that were performed for varicose veins in different European countries. CONCLUSION: There is a marked disparity across Europe between the predicted number of patients with varicose veins requiring treatment and the actual care given. The factors influencing this need more detailed investigation.

Short-term gain for long-term pain? Which patients should be treated and should we ration?

OBJECTIVES: Treatments of common conditions which do not affect mortality often become sidelined in the drive to improve efficiency and reduce costs. The rationing of patients is a divisive but crucial component to universal health care. How should this be accomplished? METHODS AND RESULTS: In this article we examine the outcomes of various rationing methods in varicose veins. CONCLUSIONS: No method is perfect and treatment of symptoms and complications should remain the target for all physicians.

Treatment options, clinical outcome (quality of life) and cost benefit (quality-adjusted life year) in varicose vein treatment.

Varicose veins are an extremely common condition causing morbidity; however, with current financial pressures, treatment of such benign diseases is controversial. Many procedures allow the treatment of varicose veins with minimal cost and extensive literature supporting differing approaches. Here we explore the underlying evidence base for treatment options, the effect on clinical outcome and the cost-benefit economics associated with varicose vein treatment. The method of defining clinical outcome with quality-of-life assessment tools is also investigated to explain concepts of treatment success beyond abolition of reflux.

Assessment of cerebrovascular autoregulation in head-injured patients: a validation study.

BACKGROUND AND PURPOSE: Cerebrovascular autoregulation is frequently measured in head-injured patients. We attempted to validate 4 bedside methods used for assessment of autoregulation. METHODS: PET was performed at a cerebral perfusion pressure (CPP) of 70 and 90 mm Hg in 20 patients. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) were determined at each CPP level. Patients were sedated with propofol and fentanyl. Norepinephrine was used to control CPP. During PET scanning, transcranial Doppler (TCD) flow velocity in the middle cerebral artery was monitored, and the arterio-jugular oxygen content difference (AJDo2) was measured at each CPP. Autoregulation was determined as the static rate of autoregulation based on PET (SROR(PET)) and TCD (SROR(TCD)) data, based on changes in AJDo2, and with 2 indexes based on the relationship between slow waves of CPP and flow velocity (mean velocity index, Mx) and between arterial blood pressure and intracranial pressure (pressure reactivity index, PRx) RESULTS: We found significant correlations between SROR(PET) and SROR(TCD) (r2=0.32; P<0.01) and between SROR(PET) and PRx (r2=0.31; P<0.05). There were no significant associations between PET data and autoregulation as assessed by changes in AJDo2. Global CMRo2 was significantly lower at the higher CPP (P<0.01). CONCLUSIONS: Despite some variability, SROR(TCD) and PRx may provide useful approximations of autoregulation in head-injured patients. At least with our methods, CMRo2 changes with the increase in CPP; hence, flow-metabolism coupling may affect the results of autoregulation testing.

A quality assurance audit: phase III trial of maximal androgen deprivation in prostate cancer (TROG 96.01).

In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme.

Very late antigen (VLA) expression by normal and neoplastic human plasma cells; including an assessment of antibodies submitted to the Vth International Workshop on Leucocyte Differentiation Antigens using human myeloma cell lines.

The biology of normal plasma cells and the pathophysiology of human multiple myeloma remain poorly understood. Functional assays are scarce and at present cell phenotyping is providing the most information about how human plasma cells may behave. Three different types of human plasma cells: normal, fresh neoplastic myeloma cells and plasma cell lines, have been studied for their reactivity with antibodies to the beta-1 integrins (Very Late Antigens; VLAs), including a panel obtained from the Vth International Workshop on Leucocyte Differentiation Antigens. Most plasma cell targets express VLA-4 (CD49d positive) and the common beta chain recognized by CD29. CD49e (VLA-5) was occasionally positive. Other VLAs were not usually expressed. These data suggest the wide use by plasma cells of VLA-4, possibly as a ligand with fibronectin and high endothelial venules (HEV). Of other adhesion structures expressed by plasma cells, only CD44 is seen as frequently, and this is also a HEV ligand.

Assessment of peritonism in appendicitis.

The aim of this study was to evaluate the accuracy of different methods of demonstrating right iliac fossa peritonism in appendicitis. The methods used were cat's eye symptom (pain on going over a bump in the road), cough sign, right iliac fossa tenderness, percussion tenderness, rebound tenderness and guarding. A series of 100 consecutive patients with a median age of 25 years (range 4-81 years), presenting with right iliac fossa pain were studied prospectively; the male:female ratio was 39:61. In all, 58 patients underwent operation, 44 had appendicitis confirmed on histology. Fourteen patients had a normal appendix removed; 11 were women aged between 16 and 45 years. Cat's eye symptom and cough sign were sensitive indicators of appendicitis (sensitivity 0.80 and 0.82, respectively), but were not specific (specificity 0.52 and 0.50, respectively) and therefore inaccurate (accuracy 64%). Percussion tenderness was less sensitive (sensitivity 0.57) but more specific (specificity 0.86). Rebound tenderness proved to be sensitive (sensitivity 0.82), specific (specificity 0.89) and accurate (accuracy 86%). Thus, rebound tenderness had a positive predictive value of 86% compared with 56% and 57% for cough sign and cat's eye symptom, respectively. In the difficult diagnostic group of young women, the positive predictive value of rebound tenderness was 88% compared with 58% and 56% for cat's eye symptom and cough sign. Appendicitis remains a difficult diagnosis, particularly in young women. Rebound tenderness still has an important role to play in clinical assessment.

Assessment of fetal-maternal haemorrhage in mothers with hereditary persistence of fetal haemoglobin.

Kleihauer examination of peripheral blood cannot be used reliably to detect transplacental fetal-maternal haemorrhage in mothers with hereditary persistence of fetal haemoglobin (HPFH). In Rh(D) negative pregnancies diagnostic confusion with a large fetal-maternal haemorrhage could result in the administration of inappropriately excessive amounts of anti-D immunoglobulin, and the inability to diagnose and quantify transplacental haemorrhage in maternal HPFH by current methods could result in insufficient anti-D administration and subsequent Rh(D) sensitisation. Accordingly, a method to detect and quantify fetal-Rh(D) positive maternal haemorrhage using erythrocyte fluorescent immunocytometry was developed. An indirect immunofluorescence method with IgG anti-D immunoglobulin as the primary antibody was used, combined with quantitative analysis on a fluorescence activated cell sorter. The method was accurate, specific, and sensitive and could detect a contaminating population of 0.1% Rh(D) positive cells in Rh(D) negative blood--a level of fetal-maternal haemorrhage well covered by a single dose of 500 IU of anti-D immunoglobulin.