David Culliford

Systemic inflammation and disease progression in Alzheimer disease

Background: Acute and chronic systemic inflammation are characterized by the systemic production of the proinflammatory cytokine tumor necrosis factor α (TNF-α) that plays a role in immune to brain communication. Previous preclinical research shows that acute systemic inflammation contributes to an exacerbation of neurodegeneration by activation of primed microglial cells. Objective: To determine whether acute episodes of systemic inflammation associated with increased TNF-α would be associated with long-term cognitive decline in a prospective cohort study of subjects with Alzheimer disease. Methods: Three hundred community-dwelling subjects with mild to severe Alzheimer disease were cognitively assessed, and a blood sample was taken for systemic inflammatory markers. Each subject’s main caregiver was interviewed to assess the presence of incident systemic inflammatory events. Assessments of both patient and caregiver were repeated at 2, 4, and 6 months. Results: Acute systemic inflammatory events, found in around half of all subjects, were associated with an increase in the serum levels of proinflammatory cytokine TNF-α and a 2-fold increase in the rate of cognitive decline over a 6-month period. High baseline levels of TNF-α were associated with a 4-fold increase in the rate of cognitive decline. Subjects who had low levels of serum TNF-α throughout the study showed no cognitive decline over the 6-month period. Conclusions: Both acute and chronic systemic inflammation, associated with increases in serum tumor necrosis factor α, is associated with an increase in cognitive decline in Alzheimer disease.

HIGH FAILURE RATES WITH A LARGE DIAMETER HYBRID METAL ON METAL TOTAL HIP REPLACEMENT: CLINICAL, RADIOLOGICAL AND RETRIEVAL ANALYSIS

This study reports the mid-term results of a large-bearing hybrid metal-on-metal total hip replacement in 199 hips (185 patients) with a mean follow-up of 62 months (32 to 83). Two patients died of unrelated causes and 13 were lost to follow-up. In all, 17 hips (8.5%) have undergone revision, and a further 14 are awaiting surgery. All revisions were symptomatic. Of the revision cases, 14 hips showed evidence of adverse reactions to metal debris. The patients revised or awaiting revision had significantly higher whole blood cobalt ion levels (p = 0.001), but no significant difference in acetabular component size or position compared with the unrevised patients. Wear analysis (n = 5) showed increased wear at the trunnion-head interface, normal levels of wear at the articulating surfaces and evidence of corrosion on the surface of the stem. The cumulative survival rate, with revision for any reason, was 92.4% (95% confidence interval 87.4 to 95.4) at five years. Including those awaiting surgery, the revision rate would be 15.1% with a cumulative survival at five years of 89.6% (95% confidence interval 83.9 to 93.4). This hybrid metal-on-metal total hip replacement series has shown an unacceptably high rate of failure, with evidence of high wear at the trunnion-head interface and passive corrosion of the stem surface. This raises concerns about the use of large heads on conventional 12/14 tapers.

Midgut neuroendocrine tumours with liver metastases: results of the UKINETS study

We intended to identify the prognostic factors and the results of interventions on patients with liver metastatic midgut carcinoids. Five institutions that are part of United Kingdom and Ireland neuroendocrine tumour (NET) group took part in this study. Patients were included if they had histology proven NET of midgut origin and liver metastases at the time of the study. Clinical and biochemical data were collected retrospectively from hospital charts, pathology reports, radiology reports and biochemistry records for each patient. Three hundred and sixty patients were included in the study. The median survival from date of diagnosis was 7.69 years (confidence interval (CI) 6.40-8.99) and 5.95 years (CI 5.02-6.88) from date of diagnosis of liver metastases. On univariate analysis, increasing age at diagnosis, increasing urinary hydroxyindole acetic acid levels, increasing plasma chromogranin A levels, high Ki67, high tumour volume and treatment with chemotherapy were identified as factors associated with a significantly poorer outcome. Resection of liver metastases, resection of small bowel primary, treatment with somatostatin analogue therapy and treatment with peptide receptor therapy were associated with improved prognosis. Multivariate analysis revealed that age at diagnosis (P=0.014), Ki67 level (P=0.039) and resection of primary (P=0.015) were independent predictors of survival. This is the largest study to our knowledge looking specifically at the prognosis and clinical course of patients with liver metastatic midgut NETs. For the first time, we have shown that Ki67 and resection of primary are independent predictors of survival for this group of patients.

Temporal trends in hip and knee replacement in the United Kingdom: 1991 TO 2006

Using the General Practice Research Database, we examined the temporal changes in the rates of primary total hip (THR) and total knee (TKR) replacement, the age at operation and the female-to-male ratio between 1991 and 2006 in the United Kingdom. We identified 27 113 patients with THR and 23 843 with TKR. The rate of performance of THR and TKR had increased significantly (p < 0.0001 for both) during the 16-year period and was greater for TKR, especially in the last five years. The mean age at operation was greater for women than for men and had remained stable throughout the period of study. The female-to-male ratio was higher for THR and TKR and had remained stable. The data support the notion that the rate of joint replacement is increasing in the United Kingdom with the rate of TKR rising at the highest rate. The perception that the mean age for TKR has decreased over time is not supported.

Proinflammatory cytokines, sickness behavior, and Alzheimer disease.

Background: In Alzheimer disease (AD), systemic inflammation is known to give rise to a delirium. However, systemic inflammation also gives rise to other centrally mediated symptoms in the absence of a delirium, a concept known as sickness behavior. Systemic inflammation is characterized by the systemic production of the proinflammatory cytokines tumor necrosis factor–α (TNFα) and interleukin-6 (IL-6) that mediate immune to brain communication and the development of sickness behavior. Objective: To determine if raised serum TNFα or IL-6 are associated with the presence of sickness behavior symptoms, independent of the development of delirium, in a prospective cohort study of subjects with AD. Methods: A total of 300 subjects with mild to severe AD were cognitively assessed at baseline and a blood sample taken for inflammatory markers. Cognitive assessments, including assessments to detect the development of a delirium, and blood samples were repeated at 2, 4, and 6 months. The development of neuropsychiatric symptoms in the subject with AD over the 6-month follow-up period was assessed independently by carer interview at 2, 4, and 6 months. Results: Raised serum TNFα and IL-6, but not CRP, were associated with an approximately 2-fold increased frequency of neuropsychiatric symptoms characteristic of sickness behavior. These relationships are independent of the development of delirium. Conclusions: Increased serum proinflammatory cytokines are associated with the presence of symptoms characteristic of sickness behavior, which are common neuropsychiatric features found in AD. This association was independent of the presence of delirium.

Etanercept in Alzheimer disease A randomized, placebo-controlled, double-blind, phase 2 trial

Objectives: To determine whether the tumor necrosis factor α inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia. Methods: In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and ClinicalTrials.gov (NCT01068353). Results: Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function. Conclusions: This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients. Classification of evidence: This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia.

Future projections of total hip and knee arthroplasty in the UK: results from the UK Clinical Practice Research Datalink

OBJECTIVE To estimate the future rate of primary total hip (THR) or knee (TKR) replacement in the UK to 2035 allowing for changes in population demographics and obesity. DESIGN Using age/gender/body mass index (BMI)-specific incidence rates from a population-based cohort study of 50,000 THR and 45,609 TKR patients from the UK Clinical Practice Research Datalink (CPRD) between 1991 and 2010, we projected future numbers of THR and TKR using two models: a static, estimated rate from 2010 applied to population growth forecasts to 2035, and a log-linear rate extrapolation over the same period. Both scenarios used population forecast data from the UK Office for National Statistics (ONS). RESULTS Assuming rates of THR and TKR for 2010, and given projected population changes in age, gender and BMI, the number of THRs and TKRs performed in the UK in 2035 is estimated to be, respectively: 95,877 and 118,666. By comparison, an exponential extrapolation of historical rates using a log-linear model produces much higher estimates of THR and TKR counts in 2035 at 439,097 and 1,219,362 respectively. Projected counts were higher for women than men. Assuming a changing (rather than fixed) future BMI distribution increases TKRs by 2035 but not THRs. CONCLUSIONS Using historical rates and population forecasts we have projected the number of THR/TKR operations in the UK up to 2035. This study will inform policymakers requiring estimates of future demand for surgery. Incorporating future forecasts for BMI into projections of joint replacement may be more relevant for TKR rather than THR.

The relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK

OBJECTIVES To evaluate the risk of aortic aneurysm in patients with giant cell arteritis (GCA) compared with age-, gender- and location-matched controls. METHODS A UK General Practice Research Database (GPRD) parallel cohort study of 6999 patients with GCA and 41 994 controls, matched on location, age and gender, was carried out. A competing risk model using aortic aneurysm as the primary outcome and non-aortic-aneurysm-related death as the competing risk was used to determine the relative risk (subhazard ratio) between non-GCA and GCA subjects, after adjustment for cardiovascular risk factors. RESULTS Comparing the GCA cohort with the non-GCA cohort, the adjusted subhazard ratio (95% CI) for aortic aneurysm was 1.92 (1.52 to 2.41). Significant predictors of aortic aneurysm were being an ex-smoker (2.64 (2.03 to 3.43)) or a current smoker (3.37 (2.61 to 4.37)), previously taking antihypertensive drugs (1.57 (1.23 to 2.01)) and a history of diabetes (0.32 (0.19 to 0.56)) or cardiovascular disease (1.98 (1.50 to 2.63)). In a multivariate model of the GCA cohort, male gender (2.10 (1.38 to 3.19)), ex-smoker (2.20 (1.22 to 3.98)), current smoker (3.79 (2.20 to 6.53)), previous antihypertensive drugs (1.62 (1.00 to 2.61)) and diabetes (0.19 (0.05 to 0.77)) were significant predictors of aortic aneurysm. CONCLUSIONS Patients with GCA have a twofold increased risk of aortic aneurysm, and this should be considered within the range of other risk factors including male gender, age and smoking. A separate screening programme is not indicated. The protective effect of diabetes in the development of aortic aneurysms in patients with GCA is also demonstrated.

The Natural History of Cranial Dural Arteriovenous Fistulae With Cortical Venous Reflux-The Significance of Venous Ectasia

BACKGROUND: The quoted risk of hemorrhage from dural arteriovenous fistulae with cortical venous reflux varies widely, and the influence of angiographic grade on clinical course has not previously been reported. OBJECTIVE: To assess the risk of hemorrhage and the influence of angiographic grade on this risk, compared with known predictors of hemorrhage such as presentation. METHODS: Seventy-five fistulae with cortical venous reflux identified in our arteriovenous malformations clinic between 1992 and 2007 were followed up clinically, and their angiograms were reviewed. RESULTS: There were 8 hemorrhages in 90 years of follow-up. The annual incidence of hemorrhage before any treatment was 13%, and 4.7% after partial treatment, giving an overall incidence of 8.9% before definitive treatment. Borden and Cognard grades were poor discriminators of risk for lesions with the exception of Cognard type IV lesions. These lesions, characterized by venous ectasia, had a 7-fold increase in the incidence of hemorrhage (3.5% no ectasia vs 27% with ectasia). Patients presenting with hemorrhage (20%) or nonhemorrhagic neurological deficit (22%) had a higher incidence of hemorrhage than those with a benign presentation (4.3%), but this may be directly linked to the presence of venous ectasia. CONCLUSION: In this series untreated dural arteriovenous fistulae with cortical venous reflux had a 13% annual incidence of hemorrhage after diagnosis. There was a significant difference between those with and without venous ectasia. This should be confirmed by further studies, but probably defines a high-risk subgroup of patients that requires rapid intervention.

Mortality in Wegener’s granulomatosis: a bimodal pattern

OBJECTIVE To characterize the long-term mortality in patients with WG compared with matched population-based controls. METHODS We used data from the General Practice Research Database, which contains the computerized records of 6.25 million patients and is representative of the population of the UK. We identified all subjects with a new diagnosis of WG in the period 1989-2004, and for each case, compared mortality with 10 controls matched for age, gender and practice. RESULTS We identified 255 patients with a new diagnosis of WG (mean age 58.1 years, range 9-90 years, 47% females) and 2546 controls (mean age 58.1 years, range 9-89 years, 47% females). Mean follow-up was 6.4 years. The mortality for patients with WG was significantly increased during the first year after diagnosis [HR 9.0 (95% CI 5.8, 13.9)], especially for those ≤ 65 years of age [HR 19.9 (95% CI 8.8, 44.9)]. The excess mortality was less marked after the first year: 1-5 years [HR 1.68 (95% CI 1.08, 2.60)], 5-10 years [HR 2.41 (95% CI 1.43, 4.07)], but started to increase by 10-15 years [HR 4.4 (95% CI 2.0, 9.8)]. The Kaplan-Meier survival curve showed an increase in mortality after 8 years. CONCLUSIONS Despite current therapy, patients with WG have a 9-fold increased risk of death in the first year of disease, attributed to infection, active vasculitis and renal failure. Between 1 and 8 years the risk is at its lowest, although higher than the control population. There is an increased mortality from 8 years onwards that remains unexplained.