A Chemical Analog of Curcumin as an Improved Inhibitor of Amyloid Abeta Oligomerization

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin

In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans

The question whether fatty acids can be converted into glucose in humans has a long standing tradition in biochemistry, and the expected answer is “No”. Using recent advances in Systems Biology in the form of large-scale metabolic reconstructions, we reassessed this question by performing a global investigation of a genome-scale human metabolic network, which had been reconstructed on the basis of experimental results. By elementary flux pattern analysis, we found numerous pathways on which gluconeogenesis from fatty acids is feasible in humans. On these pathways, four moles of acetyl-CoA are converted into one mole of glucose and two moles of CO2. Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity. This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals. Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet

Rationale, design and protocol of a longitudinal study assessing the effect of total knee arthroplasty on habitual physical activity and sedentary behavior in adults with osteoarthritis

Background: Physical activity levels are decreased and sedentary behaviour levels are increased in patients with knee osteoarthritis (OA). However, previous studies have shown that following total knee arthroplasty (TKA), objectively measured physical activity levels do not change compared to before the surgery. Very few studies have objectively assessed sedentary behaviour following TKA. This study aims to assess patterns of objective habitual physical activity and sedentary behaviour in patients with knee OA and to determine whether these change following TKA. Methods: Patients diagnosed with knee osteoarthritis and scheduled for unilateral primary total knee arthroplasty will be recruited from the Orthopaedic Division at the Charlotte Maxeke Johannesburg Academic Hospital. Eligible participants will have assessments completed one week before the scheduled arthroplasty, six weeks, and six months post-operatively. The primary outcomes are habitual physical activity and sedentary behaviour which will be measured using accelerometry (Actigraph GTX3+ and activPal monitors) at the specific time points. The secondary outcomes will be improvements in osteoarthritis-specific quality of life measures using the following questionnaires: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS), Knee Society Clinical Rating System (KSS), UCLA activity index; subjective pain scores, and self reported sleep quality.Discussion: The present study will contribute to the field of musculoskeletal health by providing a rich detailed description of the patterns of accumulation of physical activity and sedentary behaviour in patients with knee OA. These data will contribute to existing knowledge using an objective measurement for the assessment of functional ability after total knee arthroplasty. Although studies have used accelerometry to measure physical activity in knee OA patients, the data provided thus far have not delved into the detailed patterns of how and when physical activity is accumulated before and after TKA. Accurate assessment of physical activity is important for physical activity interventions that target special populations

Utilization of mechanical power and associations with clinical outcomes in brain injured patients: a secondary analysis of the extubation strategies in neuro-intensive care unit patients and associations with outcome (ENIO) trial

Background: There is insufficient evidence to guide ventilatory targets in acute brain injury (ABI). Recent studies have shown associations between mechanical power (MP) and mortality in critical care populations. We aimed to describe MP in ventilated patients with ABI, and evaluate associations between MP and clinical outcomes. Methods: In this preplanned, secondary analysis of a prospective, multi-center, observational cohort study (ENIO, NCT03400904), we included adult patients with ABI (Glasgow Coma Scale ≤ 12 before intubation) who required mechanical ventilation (MV) ≥ 24 h. Using multivariable log binomial regressions, we separately assessed associations between MP on hospital day (HD)1, HD3, HD7 and clinical outcomes: hospital mortality, need for reintubation, tracheostomy placement, and development of acute respiratory distress syndrome (ARDS). Results: We included 1217 patients (mean age 51.2 years [SD 18.1], 66% male, mean body mass index [BMI] 26.3 [SD 5.18]) hospitalized at 62 intensive care units in 18 countries. Hospital mortality was 11% (n = 139), 44% (n = 536) were extubated by HD7 of which 20% (107/536) required reintubation, 28% (n = 340) underwent tracheostomy placement, and 9% (n = 114) developed ARDS. The median MP on HD1, HD3, and HD7 was 11.9 J/min [IQR 9.2-15.1], 13 J/min [IQR 10-17], and 14 J/min [IQR 11-20], respectively. MP was overall higher in patients with ARDS, especially those with higher ARDS severity. After controlling for same-day pressure of arterial oxygen/fraction of inspired oxygen (P/F ratio), BMI, and neurological severity, MP at HD1, HD3, and HD7 was independently associated with hospital mortality, reintubation and tracheostomy placement. The adjusted relative risk (aRR) was greater at higher MP, and strongest for: mortality on HD1 (compared to the HD1 median MP 11.9 J/min, aRR at 17 J/min was 1.22, 95% CI 1.14-1.30) and HD3 (1.38, 95% CI 1.23-1.53), reintubation on HD1 (1.64; 95% CI 1.57-1.72), and tracheostomy on HD7 (1.53; 95%CI 1.18-1.99). MP was associated with the development of moderate-severe ARDS on HD1 (2.07; 95% CI 1.56-2.78) and HD3 (1.76; 95% CI 1.41-2.22). Conclusions: Exposure to high MP during the first week of MV is associated with poor clinical outcomes in ABI, independent of P/F ratio and neurological severity. Potential benefits of optimizing ventilator settings to limit MP warrant further investigation

Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury

BackgroundWe aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation of these quality indicators.MethodsA preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool.ResultsThe expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N=24, 48%) and neurosurgeons (N=7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N=49, 98%) and indicated routine measurement in registries (N=41, 82%), benchmarking (N=42, 84%), and quality improvement programs (N=41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N=48, 98%).ConclusionsThis Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future

Vibrational spectroscopy for the triage of traumatic brain injury computed tomography priority and hospital admissions

Computed tomography (CT) brain imaging is routinely used to support clinical decision-making in patients with traumatic brain injury (TBI). Only 7% of scans, however, demonstrate evidence of TBI. The other 93% of scans contribute a significant cost to the healthcare system and a radiation risk to patients. There may be better strategies to identify which patients, particularly those with mild TBI, are at risk of deterioration and require hospital admission. We introduce a blood serum liquid biopsy that utilizes attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy with machine learning algorithms as a decision-making tool to identify which patients with mild TBI will most likely present with a positive CT scan. Serum samples were obtained from patients (n = 298) patients who had acquired a TBI and were enrolled in CENTER-TBI and from asymptomatic control patients (n = 87). Injury patients (all severities) were stratified against non-injury controls. The cohort with mild TBI was further examined by stratifying those who had at least one CT abnormality against those who had no CT abnormalities. The test performed exceptionally well in classifications of patients with mild injury versus non-injury controls (sensitivity = 96.4% and specificity = 98.0%) and also provided a sensitivity of 80.2% when stratifying mild patients with at least one CT abnormality against those without. The results provided illustrate the test ability to identify four of every five CT abnormalities and show great promise to be introduced as a triage tool for CT priority in patients with mild TBI

Prediction of 60-Day Case Fatality After Aneurysmal Subarachnoid Hemorrhage: External Validation of a Prediction Model

Objective: External validation of prognostic models is crucial but rarely done. Our aim was to externally validate a prognostic model to predict 60-day case fatality after aneurysmal subarachnoid hemorrhage developed from the International Subarachnoid Aneurysm Trial in a retrospective unselected cohort of subarachnoid hemorrhage patients. Design: The model's predictors were age, aneurysm size, Fisher grade, and World Federation of Neurological Surgeons grade. Two versions of the model were validated: one with World Federation of Neurological Surgeons grade scored at admission and the other with World Federation of Neurological Surgeons grade at treatment decision. The outcome was 60-day case fatality. Performance of the model was assessed by studying discrimination, expressed by the area under the receiver operating characteristic curve, and calibration. Setting: University hospital. Patients: We analyzed data from 307 consecutive aneurysmal subarachnoid hemorrhage patients admitted between 2007 and 2011 (validation cohort). Interventions: None. Measurements and Main Results: The observed 60-day case fatality rate was 30.6%. Discrimination was good, and differed between the model with World Federation of Neurological Surgeons grade at treatment decision (area under the receiver operating characteristic curve, 0.89) and at admission (area under the receiver operating characteristic curve, 0.82). Mean predicted probabilities were lower than observed: 17.0% (model with World Federation of Neurological Surgeons grade at admission) and 17.7% (model with World Federation of Neurological Surgeons grade at treatment decision). Conclusions: The model discriminated well between patients who died or survived within 60 days. In addition, we found that using World Federation of Neurological Surgeons grade at moment of treatment decision of the ruptured aneurysm improved model performance. However, since predicted probabilities were much lower than observed probabilities, the International Subarachnoid Aneurysm Trial prediction model needs to be adapted to be used in clinical practice