Course Review: Yorkshire Microsurgery Course 2023.

ABSTRACT: Microsurgery is an advanced set of techniques that require a high level of skill to be performed safely. Surgical skills courses offer safe environments for practice in such skills and form a fundamental part of surgical training. The Yorkshire Microsurgery Course is a 3-day course at Bradford Royal Infirmary, United Kingdom. Delivered via short lectures followed by supervised practical sessions, the course aims to provide delegates with the essential knowledge and skills required for microsurgery.We detail an outline and critical evaluation of the February 2023 iteration of the course, with recommendations for improvement.Overall, we found the course excellent. It provided delegates with a solid grounding in the fundamentals of microsurgery and the opportunity for personalized practice supervised by experts. We would recommend this course to colleagues interested in a career in plastic surgery.

Safety of Large-Volume Liposuction in Aesthetic Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Current literature clearly outlines the complication rates of liposuction in general; however, data specific to large-volume liposuction (LVL) remain unclear. OBJECTIVES: The authors aimed to synthesize the current evidence on the safety of LVL with this systematic review. METHODS: A comprehensive search in the MEDLINE, EMBASE, and CENTRAL databases was conducted for primary clinical studies reporting on safety or complications related to aesthetic LVL from 1946 to March 2020. The primary outcome measure was the incidence of surgical complication, and the secondary outcome measure was changes in metabolic profile. Meta-analyses were conducted to pool the estimated surgical complication incidence and metabolic changes. RESULTS: Twenty-three articles involving 3583 patients were included. The average aspirate volume was 7734.90 mL (95% CI = 5727.34 to 9742.45 mL). The pooled overall incidence of major surgical complications was 3.35% (95% CI = 1.07% to 6.84%). The most common major complication was blood loss requiring transfusion (2.89% [95% CI = 0.84% to 6.12%]) followed by pulmonary embolism (0.18% [95% CI = 0.06% to 0.33%]), hematoma (0.16% [95% CI = 0.05% to 0.32%]), necrotizing fasciitis (0.13% [95% CI = 0.04% to 0.29%]), and deep vein thrombosis (0.12% [95% CI = 0.03% to 0.27%]). No fat embolism or death was reported in the included studies. The pooled overall incidence of minor surgical complication was 11.62% (95% CI = 6.36% to 18.21%), with seroma being the most common minor complication (5.51% [95% CI = 2.69% to 9.27%]). Reductions in lipid profile, glucose profile, body weight, and hematocrit level were observed after LVL. CONCLUSIONS: The authors meta-analyzed and highlighted the complication rates specifically related to LVL in this study; however, the current data are limited by the lack of level 1 evidence.

The emerging role of robotics in plastic and reconstructive surgery: a systematic review and meta-analysis.

The role of robotics has grown exponentially. There is an active interest amongst practitioners in the transferability of the potential benefits into plastic and reconstructive surgery; however, many plastic surgeons report lack of widespread implementation, training, or clinical exposure. We report the current evidence base, and surgical opportunities, alongside key barriers, and limitations to overcome, to develop the use of robotics within the field. This systematic review of PubMed, Medline, and Embase has been conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PROSPERO (ID: CRD42024524237). Preclinical, educational, and clinical articles were included, within the scope of plastic and reconstructive surgery. 2, 181, articles were screened; 176 articles met the inclusion criteria across lymph node dissection, flap and microsurgery, vaginoplasty, craniofacial reconstruction, abdominal wall reconstruction and transoral robotic surgery (TOR). A number of benefits have been reported including technical advantages such as better visualisation, improved precision and accuracy, and tremor reduction. Patient benefits include lower rate of complications and quicker recovery; however, there is a longer operative duration in some categories. Cost presents a significant barrier to implementation. Robotic surgery presents an exciting opportunity to improve patient outcomes and surgical ease of use, with feasibility for many subspecialities demonstrated in this review. However, further higher quality comparative research with careful case selection, which is adequately powered, as well as the inclusion of cost-analysis, is necessary to fully understand the true benefit for patient care, and justification for resource utilisation.

A comparison of commercially available synthetic skin substitutes for surgical simulation training.

Objective: Simulation training provides an important opportunity to accelerate surgical skills acquisition whilst safeguarding patients. This study compares the suitability of different synthetic skin substitutes for use in surgical simulation training. Design: Data was collected for eight commercially available synthetic skin substitutes and included cost, delivery time, subjective assessment of fidelity by surgeons and trainees, and objective comparison with the biomechanics of human skin was made through cutometry and durometry measurements. Cutometry and durometry data was collected from three healthy adults from the forearm, forehead and back, with measurements being repeated in triplicate. Subjective assessment of skin pad quality was collected using an 8-criteria questionnaire, graded using a 5-point Likert scale for fidelity to normal skin. Results: The questionnaire assessment was completed by 30 trainees and practitioners. Overall, felt pads received the poorest outcomes in all criteria; cutometry and durometry results demonstrate poor similarity to skin, and felt received the lowest scores in the questionnaire, although the cheapest. Foam dressings were similar in both cutometric and durometric properties to skin of the face, back and arm. Clinical outcomes of foam dressings were similar to the most expensive commercial skin pad. Conclusions: Bilaminar foam-based dressings provide a low cost, high fidelity non-biological simulation of skin for surgical training, which is non-inferior to more expensive specifically designed products. Many products designed to act as skin substitutes for surgical simulation fail to adequately replicate the anatomical and mechanical properties of skin.

The intraoperative use of augmented and mixed reality technology to improve surgical outcomes: A systematic review.

BACKGROUND: This systematic review aims to critically appraise the intraoperative use of augmented and mixed reality technology to improve surgical outcomes. METHOD: A literature search of PubMed, Scopus, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO ICTRP was performed in accordance with Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: This review included 94 studies on 2473 patients, comprising 78 studies on augmented reality and 16 on mixed reality. This technology has seen broad intraoperative application. Augmented and mixed reality can reduce operative duration, blood loss, and the duration of inpatient care. Current evidence shows that they achieve this most in percutaneous surgery. CONCLUSIONS: Augmented and mixed reality technology improve surgical outcomes by increasing navigational speed and reducing navigational error intraoperatively. However, they have technical limitations which are the subject of ongoing research. Further studies are necessary to define how this technology is best applied intraoperatively. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020205892.

Patient-reported outcome and cost implication of acute salvage of infected implant-based breast reconstruction with negative pressure wound therapy with Instillation (NPWTi) compared to standard care.

INTRODUCTION: Implant loss due to infection is the most devastating complication of implant-based breast reconstruction. The use of negative pressure wound therapy with instillation(NPWTi) for salvage of infected implant-based breast reconstructions has shown promising results allowing early reinsertion of a new implant as an alternative to the current management with delayed reinsertion. This study compares the patient-reported outcome and cost implication of NPWTi to the current management. METHODS: Twenty cases of infected breast implants treated with NPWTi(V.A.C. VERAFLO™ Therapy), followed by early reinsertion of new implants were compared to 20 cases that had delayed reinsertion(non-NPWTi). Patient satisfaction was evaluated using the BREAST-Q questionnaire. The average cost per patient was calculated using total operative expense, cost of inpatient stay, investigations, antibiotics, and outpatient visits. RESULTS: Treatment with NPWTi allowed earlier reinsertion of a new implant (NPWTi: 10.3 ± 2.77days vs. non-NPWTi: 247.45±111.28days, p<0.001). Patients in the NPWTi group reported higher satisfaction. The average cost per patient for NPWTi and non-NPWTi was £14,343.13±£2,786.70 and £8,920.31±£3,005.73, respectively(p<0.001). All patients treated with NPWTi had one admission and spent 11.9 ± 4.1days as inpatients, while non-NPWTi patients had 2.1 ± 0.3 admissions(p<0.001) and spent 7.1 ± 5.8days(p<0.004) as inpatients. Patients treated with NPWTi had more procedures (NPWTi:3.35±0.81 Vs. non-NPWTi:2.2 ± 0.41, p = 0.006); however, three non-NPWTi cases required flap reconstruction. CONCLUSION: Patients treated with NPWTi reported higher satisfaction, received a new and earlier implant, and had fewer admissions and outpatient visits; however, they incurred higher average costs, longer inpatient stays, and underwent more procedures. Early implant reinsertion preserves skin envelope; hence avoiding additional cost and stress related to further major autologous reconstruction.

C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required. METHODS AND RESULTS: Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n=865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n=5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P<0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit. CONCLUSIONS: Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.

Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: Statins are important in vascular disease prevention in the elderly. However, the best method of selecting older patients for treatment is uncertain. We assessed the role of plasma lipoproteins as predictors of risk and of treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). METHOD AND RESULTS: The association of LDLc and HDLc with risk was examined in the 5804 70- to 82-year-old subjects of PROSPER. Baseline LDLc showed no relation to risk of the primary end point in the placebo group (P=0.27), nor did on-treatment LDLc in the pravastatin group (P=0.12). HDLc was inversely associated with risk in subjects on placebo (P=0.0019) but not in those on pravastatin (P=0.24). Risk reduction on pravastatin treatment was unrelated to baseline LDLc (P=0.38) but exhibited a significant interaction with HDLc (P=0.012). Subjects in the lowest 2 quintiles of HDLc (<1.15 mmol/L) had a risk reduction of 33% (hazard ratio, 0.67; 95% confidence limits, 0.55, 0.81; P<0.0001), whereas those with higher HDLc showed no benefit (RR, 1.06; 95% confidence limits, 0.88, 1.27; P=0.53). During follow-up, there was no relation between achieved level of LDLc or HDLc and risk. However, the change in the LDLc/HDLc ratio on statin treatment appeared to account for the effects of therapy. CONCLUSIONS: In people >70 years old, HDLc appears to be a key predictor of risk and of treatment benefit. Findings in PROSPER suggest that statin therapy could usefully be targeted to those with HDLc <1.15 mmol/L or an LDLc/HDLc ratio >3.3.

Transesophageal echocardiography is superior to transthoracic echocardiography in management of patients of any age with transient ischemic attack or stroke.

BACKGROUND AND PURPOSE: The merits of transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) in the management of transient ischemic attack (TIA) and stroke patients remains matter of debate. METHODS: Two hundred and thirty-one consecutive patients with a recent TIA or stroke for which no definite cause and indication for anticoagulation was assessed after standardized work-up underwent TTE and TEE. Echocardiographic findings were categorized into minor and major risk factors. RESULTS: A potential cardiac source of embolism was detected in 55% (127/ 231) of the patients by echocardiography, in 39% (90/231) only identified on TEE. Major risk factors, with an absolute indication for oral anticoagulation, were detected in 20% (46/231) of the patients, in 16% (38/231) of all patients identified on TEE only. A thrombus in the left atrial appendage was the most common major risk factor (38 patients, 16%). The presence of major risk factors was independent of age (chi2=1.48; P=0.224). The difference in proportions of cardiac sources detected in favor of TEE was highly significant in both patients < or = 45 years of age (10/39, P=0.002) and in those > 45 years of age (80/192; P<0.004). CONCLUSIONS: TEE proved superior to TTE for identification of a cardiac embolic source in patients with TIA or stroke without pre-existent indication or contraindication for anticoagulation. In patients with normal TTE, a cardiac source of embolism was detected by TEE in approximately 40% of patients, independent of age. More than 1 of 8 patients of any age with normal TTE revealed a major cardiac risk factor on TEE, in whom anticoagulation is warranted.

Lack of effect of pravastatin on cerebral blood flow or parenchymal volume loss in elderly at risk for vascular disease.

BACKGROUND AND PURPOSE: Ageing is associated with a decline in cerebral blood flow. Animal studies have shown that cholesterol-lowering therapy with statins might preserve cerebral blood flow (CBF). We examined the effect of 40 mg pravastatin on the decline in CBF and brain volume in a subset of elderly subjects participating in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. METHODS: Randomization was not stratified according to whether or not subjects participated in the MRI substudy. In 391 men (n=226) and women (n=165) aged 70 to 82 years (mean+/-SD, 75+/-3.2), we measured total CBF (in mL/min) at baseline and after a mean+/-SD follow-up of 33+/-1.4 months with a gradient-echo phase-contrast MRI technique. Total CBF was defined as the summed flows in both internal carotid and vertebral arteries. Parenchymal volume (whole brain) was segmented with the use of in-house-developed semiautomatic software. RESULTS: Total CBF significantly declined in the placebo-allocated group, from 521+/-83 to 504+/-92 mL/min (P=0.0036) and in the pravastatin-allocated group from 520+/-94 to 506+/-92 mL/min (P=0.018). This decline was not significantly different between treatment groups (P=0.56). There was also a significant reduction in brain volume over time (P<0.001), which was not different between the treatment groups (P=0.47). When expressed per unit of parenchymal volume, the decline in CBF over time was no longer statistically significant. CONCLUSIONS: Elderly people at risk for cerebral vascular disease had a significant decline in CBF with increasing age that was explained by a concomitant reduction in brain volume. Treatment with 40 mg pravastatin daily had no beneficial effect on total CBF.

Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies have shown an increased risk of venous thrombosis in women taking third-generation oral contraceptives, ie, those containing the progestogens desogestrel or gestodene. This study assesses the risk of ischemic stroke with several types of oral contraceptives. METHODS: A multicenter, population-based, case-control study was performed in 9 Dutch centers in women aged 18 to 49 years. Women with a first ischemic stroke were compared with control women without vascular diseases. The control subjects were recruited by random-digit dialing and were stratified by age, area of residence, and year of stroke. All patients and control subjects filled in a questionnaire about the use of oral contraceptives and risk factors for ischemic stroke. Odds ratios were adjusted for the stratification factors. RESULTS: Two hundred three women with an ischemic stroke and 925 control women were included. The risk of stroke in women using any type of oral contraceptives versus none was 2.3 (95% CI 1.6 to 3.3). Current users of first-generation oral contraceptives had an odds ratio of 1.7 (95% CI 0.7 to 4.4). Low-dose second-generation oral contraceptives increased the risk of stroke 2.4 times (95% CI 1.6 to 3.7), and third-generation oral contraceptives increased the risk of stroke 2.0 times (95% CI 1.2 to 3.5). The risk of stroke in women using third-generation oral contraceptives was not different from that in women using second-generation oral contraceptives (odds ratio 1.0, 95% CI 0.6 to 1.8). CONCLUSIONS: Third-generation oral contraceptives (containing desogestrel or gestodene) confer the same risk of first ischemic stroke as second-generation oral contraceptives (containing levonorgestrel).

Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans.

Nitric oxide (NO) plays a pivotal role in the regulation of peripheral vascular tone. Its role in the regulation of cerebral vascular tone in humans remains to be elucidated. This study investigates the role of NO in hypoxia-induced cerebral vasodilatation in young healthy volunteers. The effect of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on the cerebral blood flow (CBF) was assessed during normoxia and during hypoxia (peripheral O(2) saturation 97 and 80%, respectively). Subjects were positioned in a magnetic resonance scanner, breathing normal air (normoxia) or a N(2)-O(2) mixture (hypoxia). The CBF was measured before and after administration of L-NMMA (3 mg/kg) by use of phase-contrast magnetic resonance imaging techniques. Administration of L-NMMA during normoxia did not affect CBF. Hypoxia increased CBF from 1,049 +/- 113 to 1,209 +/- 143 ml/min (P < 0.05). After L-NMMA administration, the augmented CBF returned to baseline (1,050 +/- 161 ml/min; P < 0.05). Similarly, cerebral vascular resistance declined during hypoxia and returned to baseline after administration of L-NMMA (P < 0.05 for both). Use of phase-contrast magnetic resonance imaging shows that hypoxia-induced cerebral vasodilatation in humans is mediated by NO.

A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics.

BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.

Shape abnormalities of the striatum in Alzheimer's disease.

Postmortem studies show pathological changes in the striatum in Alzheimer's disease (AD). Here, we examine the surface of the striatum in AD and assess whether changes of the surface are associated with impaired cognitive functioning. The shape of the striatum (n. accumbens, caudate nucleus, and putamen) was compared between 35 AD patients and 35 individuals without cognitive impairment. The striatum was automatically segmented from 3D T1 magnetic resonance images and automatic shape modeling tools (Growing Adaptive Meshes) were applied for morphometrical analysis. Repeated permutation tests were used to identify locations of consistent shape deformities of the striatal surface in AD. Linear regression models, corrected for age, gender, educational level, head size, and total brain parenchymal volume were used to assess the relation between cognitive performance and local surface deformities. In AD patients, differences of shape were observed on the medial head of the caudate nucleus and on the ventral lateral putamen, but not on the accumbens. The head of the caudate nucleus and ventral lateral putamen are characterized by extensive connections with the orbitofrontal and medial temporal cortices. Severity of cognitive impairment was associated with the degree of deformity of the surfaces of the accumbens, rostral medial caudate nucleus, and ventral lateral putamen. These findings provide evidence for the hypothesis that in AD primarily associative and limbic cerebral networks are affected.

Decline in total cerebral blood flow is linked with increase in periventricular but not deep white matter hyperintensities.

PURPOSE: To retrospectively investigate the association between changes in total cerebral blood flow and progression of total, periventricular, and deep white matter hyperintensities over time. MATERIALS AND METHODS: The institutional ethics review board approved the protocol for the prospective magnetic resonance (MR) imaging study, and all participants gave written informed consent. Participants also agreed to future retrospective analysis of their MR data for research purposes. In this substudy of the Prospective Study of Pravastatin in the Elderly at Risk, investigators performed a repeated MR imaging examination after an average interval of 33 months (standard deviation, 1.4) in 390 elderly men and women (ages 70-82 years at baseline) without dementia who were at high vascular risk. White matter hyperintensities were quantified with a semiautomatic method, and total cerebral blood flow was measured with a gradient-echo phase-contrast MR imaging technique. The association between total cerebral blood flow and volume of white matter hyperintensities was analyzed with logistic regression. RESULTS: There was no association between baseline cerebral blood flow and prevalence of total, periventricular, or deep white matter hyperintensities at baseline MR imaging. Moreover, decline in cerebral blood flow was not associated with increase in total load of white matter hyperintensities. When the total volume of white matter hyperintensities was separated into periventricular and deep hyperintensities, for every 50 mL/min decrease in total cerebral blood flow there was a 1.32 (95% confidence interval: 1.06, 1.66; P = .015) increase in risk for developing periventricular white matter hyperintensities; there was no association, however, between decrease in total cerebral blood flow and risk of developing deep white matter hyperintensities (odds ratio, 1.00 [95% confidence interval: 0.79, 1.25]; P = .98). CONCLUSION: Decline in total cerebral blood flow is associated with increase in volume of periventricular but not deep white matter hyperintensities.

Association between apolipoprotein E4 and cognitive decline in elderly adults.

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. DESIGN: Prospective study. SETTING: Scotland, Ireland, and the Netherlands. PARTICIPANTS: Five thousand eight hundred four subjects aged 70 to 82 from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). MEASUREMENTS: Subjects were assessed at baseline and over a mean 3.2-year (range 0.7-4.2) follow-up for memory (Picture-Word Recall), speed of information processing (Stroop and Letter-Digit Coding), global cognitive function (Mini-Mental State Examination), and activities of daily living. RESULTS: At baseline, subjects with apolipoprotein E(4) versus those without E(4) had poorer memory performance (mean score difference -0.20 (95% confidence interval (CI)=-0.31 to -0.09) for immediate recall and -0.32 (95% CI=-0.48 to -0.16) for delayed recall and slower information processing (difference in Stroop, 2.79 seconds, (95% CI=1.20-4.28); Letter-Digit score, -0.36, (95% CI=-0.77-0.05). Subjects with apolipoprotein E(4) showed a greater decline in immediate (-0.22, 95% CI=-0.33 to -0.11) and delayed (-0.30, 95% CI=-0.46 to -0.15) memory scores but no significant change in speed of information processing (Stroop, P=.17; Letter-Digit, P=.06). Memory scores decreased 2.5% from baseline in those without E(4), 4.3% in E(4) heterozygotes (P=.01 for immediate and P=.03 for delayed, vs no E(4)) and 8.9% to 13.8% in E(4) homozygotes (P=.04 for immediate and P=.004 for delayed, vs heterozygotes). Apolipoprotein E(4) was associated with greater decline in instrumental activities of daily living (P<.001). Cognitive decline was not associated with lipoprotein levels. CONCLUSION: Findings in PROSPER indicate that E(4) is associated with more-rapid cognitive decline and may, therefore, predispose to dementia.

Detection of a soluble form of BACE-1 in human cerebrospinal fluid by a sensitive activity assay.

BACKGROUND: Formation of deposits of the insoluble amyloid beta-peptide is believed to be causally related with neurodegeneration in Alzheimer disease (AD). The beta-peptide originates from a larger amyloid precursor protein (APP) by the action of proteolytic enzymes. The first proteolytic event leading to amyloid formation is the cleavage of APP by the membrane-bound aspartyl protease BACE-1, also known as memapsin-2. Inhibition of BACE-1 is thought to be a therapeutic approach to AD. Measuring BACE-1 activity in biological samples would be useful to elucidate the mechanism of AD and for development of AD drugs. METHODS: We developed a sensitive and specific activity assay for BACE-1. The assay is based on a genetically engineered proenzyme that is specifically activated by BACE-1. The resulting active enzyme is measured with a chromogenic substrate. The use of 2 coupled reactions produces a detection limit as low as 0.4 pmol/L. RESULTS: The assay detected BACE-1 activity in extracts of human brain tissue as well as, unexpectedly, in human cerebrospinal fluid (CSF). Gel electrophoresis and Western blotting identified the BACE-1 present in CSF as a truncated soluble form of the originally membrane-bound BACE-1. CONCLUSION: Detection of the soluble form of BACE-1 in CSF, a relatively easily accessible biological fluid, may be useful for monitoring the effects of drug candidates in vivo and may have diagnostic or prognostic applications.

MR assessment of cerebral vascular response: a comparison of two methods.

PURPOSE: To compare the results and reproducibility of two MR-based methods of measuring the cerebrovascular response (CVR). MATERIALS AND METHODS: In eight volunteers, CVR was assessed with two MR-based methods upon a challenge with acetazolamide. CVR was assessed by measuring changes in total cerebral blood flow (TCBF) using phase contrast (PC) MRI, and by measuring perfusion MRI. To assess reproducibility the measurements were repeated after 1 week. RESULTS: The average CVR with the PC-MRI method was 46% (SD = 16%), and for perfusion MR the measured CVR was 44% (SD = 16%). The coefficient of variation (COV) for PC-MRI was 28%, while perfusion MR had a COV of 26%. The limits of agreement between the two methods were -49% and 45%, demonstrating a lack of agreement between the two methods in terms of CVR estimation. CONCLUSION: CVR estimates based on PC-MRI and perfusion MRI showed reproducibility but a lack of agreement in healthy volunteers. This lack of agreement can be attributed to the different aspects of the CVR reflected by these methods: TCBF reflects changes in CBF, whereas our perfusion MRI method reflects cerebral blood volume (CBV).

Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.

BACKGROUND: Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. METHODS: We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. FINDINGS: Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. INTERPRETATION: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.