Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression.

The microtubule-associated protein Tau plays a critical role in the pathogenesis of Alzheimer disease and several related disorders (tauopathies). In the disease Tau aggregates and becomes hyperphosphorylated forming paired helical and straight filaments, which can further condense into higher order neurofibrillary tangles in neurons. The development of this pathology is consistently associated with progressive neuronal loss and cognitive decline. The identification of tractable therapeutic targets in this pathway has been challenging, and consequently very few clinical studies addressing Tau pathology are underway. Recent active immunization studies have raised the possibility of modulating Tau pathology by activating the immune system. Here we report for the first time on passive immunotherapy for Tau in two well established transgenic models of Tau pathogenesis. We show that peripheral administration of two antibodies against pathological Tau forms significantly reduces biochemical Tau pathology in the JNPL3 mouse model. We further demonstrate that peripheral administration of the same antibodies in the more rapidly progressive P301S tauopathy model not only reduces Tau pathology quantitated by biochemical assays and immunohistochemistry, but also significantly delays the onset of motor function decline and weight loss. This is accompanied by a reduction in neurospheroids, providing direct evidence of reduced neurodegeneration. Thus, passive immunotherapy is effective at preventing the buildup of intracellular Tau pathology, neurospheroids, and associated symptoms, although the exact mechanism remains uncertain. Tau immunotherapy should therefore be considered as a therapeutic approach for the treatment of Alzheimer disease and other tauopathies.

Outcomes after transaortic transcatheter aortic valve implantation: long-term findings from the European ROUTE†.

OBJECTIVES: There is lack of data regarding the longer-term outcomes of patients undergoing transaortic (TAo) transcatheter aortic valve implantation (TAVI). We aimed to provide a contemporary snapshot of the types and frequencies of events in the year following TAo-TAVI. METHODS: The Registry of the Utilization of the TAo-TAVI approach using the Edwards SAPIEN Valve (ROUTE) is a multicentre, European, prospective, observational registry of aortic stenosis patients undergoing TAo-TAVI. Patients were grouped according to the composite end point death, myocardial infarction, stroke/transient ischaemic attack, major vascular complications, life-threatening bleeding, acute kidney injury (AKI) and/or cardiovascular rehospitalization. RESULTS: Two hundred and fifty-three patients with a mean age of 81.5 ± 5.8 years were included, of whom 89 (35.2%) patients met the composite end point (the event group) and 164 (64.8%) patients did not (the event-free group). New York Heart Association (NYHA) class III/IV (85.2% vs 71.8%, P = 0.017), Canadian Cardiovascular Society angina class III/IV (22.6% vs 11.4%; P = 0.021), pulmonary disease (32.6% vs 18.9%; P = 0.015) and renal insufficiency (15.7% vs 3.0%; P < 0.001) were more common in the event group. At 1 year, the most common event was death (19.1%), followed by AKI stage II or III (14.7%). The baseline renal insufficiency was the strongest independent predictor of composite end point achievement [odds ratio (OR) 7.55, 95% confidence interval (CI) 2.33-24.56], followed by NYHA class III/IV (OR 2.316, 95% CI 1.06-5.06) and pulmonary disease (OR 2.91, 95% CI 1.45-5.85). Pulmonary disease was also an independent predictor of 1-year mortality (OR 3.01, 95% CI 1.34-6.75). CONCLUSIONS: Long-term outcomes after TAo-TAVI appear to be similar to those for TAVI via other non-transfemoral access routes. Awareness of characteristics associated with poorer outcomes may aid patient selection and identification of those requiring closer post-procedural monitoring. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT01991431.

Unusual presentation of pancreatitis with extrapancreatic manifestations.

Pancreatitis, panniculitis and polyarthritis syndrome (PPP syndrome) is a rare and complex manifestation of pancreatitis that is currently reported in few cases. We present this case regarding a 77-year-old man who presented unusually with a 6-week history of bilateral lesions on his lower limbs. During this time, he experienced increasing fatigue, joint pain, and reported fevers and significant weight loss. An incidental serum amylase was found to be significantly elevated and remained elevated throughout his 2-month hospital stay. He never complained of abdominal pain or other typical symptoms of pancreatitis. Histological examination of the leg lesions reported evidence of fat necrosis and changes consistent with pancreatic panniculitis. An abdominal CT scan revealed a well-defined lesion posterior to the neck of the pancreas. Further examination by endoscopic ultrasound revealed chronic inflammatory changes. The patient experienced a long admission and was managed supportively until he was well enough to be discharged home.

Fixed-dose vs free-dose combinations for the management of hypertension-An analysis of 81 958 patients.

Fixed-dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed-dose or free-dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease.

Impact of Rehabilitation on Outcomes after TAVI: A Preliminary Study.

The benefit of rehabilitation in elderly patients undergoing transcatheter aortic valve implantation (TAVI) for treatment of severe aortic stenosis is unknown. The impact of declining rehabilitation programs on mortality has also not been described. In a longitudinal cohort study of 1056 patients undergoing elective TAVI between 2008 and 2016, logistic regression analysis was used to assess the relationship between treatment modality and outcome according to whether or not patients participated in a three-week rehabilitation program after TAVI. Subgroup analyses included patient outcome separated according to cardiac, geriatric, or no rehabilitation. A total of 1017 patients survived until hospital discharge (96.3%) and were offered rehabilitation, 366 patients (36.0%) declined to undergo rehabilitation, with the remaining patients undergoing either cardiac (n = 435; 42.8%) or geriatric rehabilitation (n = 216; 21.2%). Mortality at six months was lower for patients receiving rehabilitation compared with those who had not (adjusted odds ratio (OR): 0.49; 95% confidence interval (confidence interval [CI]: 0.25⁻0.94; p = 0.032). Sub-analysis showed the benefit of cardiac (adjusted OR: 0.31; 95% CI 0.14⁻0.71, p = 0.006), but not geriatric rehabilitation (adjusted OR 0.83; 95% CI 0.37⁻1.85, p = 0.65). A program of rehabilitation after TAVI has the potential to reduce mortality. Future studies should focus on health-orientated behavior and identifying risk factors for declining rehabilitation programs.

The polypill: An effective approach to increasing adherence and reducing cardiovascular event risk.

Background Despite a wide range of medications being available for the prevention of cardiovascular events such as stroke, myocardial infarction and mortality in both a primary and secondary setting, patient adherence to complex therapy regimens involving different drug classes remains low worldwide. Combining antiplatelet, antihypertensive, lipid-lowering and potentially further drugs into one 'polypill' has the potential to increase adherence, thereby reducing risk factors to a greater extent and for a longer duration. The World Health Organization has recently highlighted increased adherence as a key development need for reducing cardiovascular disease. Methods Recent clinical trial data regarding adherence, reductions in cardiovascular risk and outcomes, safety and tolerability and the cost-effectiveness of the polypill approach are summarised and reviewed. In addition, ongoing trials and the questions they intend to answer are considered. References were retrieved from a PubMed literature search (date range 1990-2016) using the terms 'polypill', 'cardiovascular events' and 'adherence', and selected based on relevance. The website www.clinicaltrials.gov was also consulted for the identification of ongoing trials. Conclusions To date, the polypill approach has been conclusively shown to increase adherence relative to usual care in all patients, with those in a primary care setting or with poor baseline adherence potentially standing to benefit most. Concomitant risk factor reductions have also been suggested. However, whether this translates into a reduction in cardiovascular events and generates good cost-effectiveness in a given healthcare environment is currently under further investigation.

The factor xa inhibitor edoxaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

INTRODUCTION: With the rising prevalence of nonvalvular atrial fibrillation (NVAF) in the general population, the development of new drugs for prevention of thromboembolic events is essential. Non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to present a number of advantages over conventionally used agents, such as predictable pharmacokinetics and no requirement for continuous anticoagulant monitoring. The most recently approved NOAC for the NVAF indication is edoxaban. Several subgroup analyses from the edoxaban phase III ENGAGE AF-TIMI 48 trial have now been published, alongside meta-analysis data comparing the four currently approved NOACs. Consequently, an updated review of the literature is merited. Areas covered: A PubMed search using the terms 'edoxaban', 'non-vitamin K antagonist oral anticoagulant', 'ENGAGE AF-TIMI 48', and 'atrial fibrillation' was performed and results screened for the most relevant English language publications. The market position, pharmacological profile, clinical efficacy, safety and tolerability of edoxaban are presented and discussed. Expert commentary: Edoxaban has been shown to have an efficacy similar or superior to that of warfarin, with a potentially lower risk of major bleeding and predictable, dose-dependent pharmacology. In order to clarify its position within the NOAC market, head-to-head comparative studies are required.

The value of biochemical markers in predicting a perforation in acute appendicitis.

BACKGROUND: Acute appendicitis is the most common surgical diagnosis of abdominal pain. Perforated appendicitis can result in increased morbidity and mortality. Identifying a perforation early can reduce the impact on the patient. Bilirubin, C-reactive protein (CRP) and white cell count (WCC) have been shown to indicate perforation in appendicitis. This study aimed to identify whether these biochemical markers can be used to identify if patients are suitable for either a conservative or surgical approach. METHODS: A retrospective post hoc analysis of all appendicectomies over a 6-year period investigating the association between preoperative bilirubin, CRP, WCC, and neutrophil count and the histological findings of either the presence or lack of a perforation. RESULTS: One thousand two hundred seventy-one patients had appendicitis, 154 (12.12%) of which were perforated upon histological examination. All biochemical markers were significantly higher in perforation (P < 0.001). The greatest sum of sensitivity and specificity of CRP was at 34.6 mg/L (sensitivity 78.57%, specificity 63.01%), and for bilirubin was at 21.5 µmol/L (sensitivity 62.96%, specificity 88.31%). Combining CRP and bilirubin improved sensitivity and specificity, but this was reduced by further incorporating WCC and neutrophils. Logistic regression analysis identified CRP as the most sensitive marker of perforation (odds ratio (OR) = 1.064 (1.043-1.085) ) (P < 0.001), with bilirubin (OR = 1.005 (1.003-1.008) ) also significant (P < 0.001) for a 1-unit increase. CONCLUSION: Bilirubin and CRP are markers of perforation in appendicitis, but are not accurate enough to be diagnostic. In a patient with high clinical suspicion of acute appendicitis, a raised CRP and bilirubin suggests that a patient is not suitable for conservative treatment.

Molecular analysis of peroxisome proliferation in the hamster.

Three novel P450 members of the cytochrome P450 4A family were cloned as partial cDNAs from hamster liver, characterised as novel members of the CYP4A subfamily, and designated CYP4A17, 18, and 19. Hamsters were treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, methylclofenapate (MCP) or Wy-14,643, and shown to develop hepatomegaly and induction of CYP4A17 RNA, and concomitant induction of lauric acid 12- hydroxylase. This treatment also resulted in hypolipidaemia, which was most pronounced in the VLDL fraction, with up to 50% reduction in VLDL-triglycerides; by contrast, blood cholesterol concentration was unaffected by this treatment. These data show that hamster is highly responsive to induction of CYP4A by peroxisome proliferators. To characterise the molecular basis of peroxisome proliferation, the hamster PPARalpha was cloned and shown to encode a 468-amino-acid protein, which is highly similar to rat and mouse PPARalpha proteins. The level of expression of hamster PPARalpha in liver is intermediate between mouse and guinea pig. These results fail to support the hypothesis that the level of PPARalpha in liver is directly responsible for species differences in peroxisome proliferation.