Molecular insights into the primary nucleation of polymorphic amyloid ß dimers in DOPC lipid bilayer membrane.

Alzheimer's disease (AD) pathology is characterized by loss of memory cognitive and behavioral deterioration. One of the hallmarks of AD is amyloid ß (Aß) plaques in the brain that consists of Aß oligomers and fibrils. It is accepted that oligomers, particularly dimers, are toxic species that are produced extracellularly and intracellularly in membranes. It is believed that the disruption of membranes by polymorphic Aß oligomers is the key for the pathology of AD. This is a first study that investigate the effect of polymorphic "α-helix/random coil" and "fibril-like" Aß dimers on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane. It has been found that the DOPC membrane promotes Aß1-42 "fibril-like" dimers and impedes Aß1-42 "α-helix/random coil" dimers. The N-termini domains within Aß1-42 dimers play a role in Aß aggregation in membrane milieus. In addition, the aromatic π-π interactions (involving residues F19 and F20 in Aß1-42 ) are the driving forces for the hydrophobic interactions that initiate the primary nucleation of polymorphic Aß1-42 dimers within DOPC membrane. Finally, the DOPC bilayer membrane thickness is locally decreased, and it is disrupted by an embedded distinct Aß1-42 dimer, due to relatively large contacts between Aß1-42 monomers and the DOPC membrane. This study reveals insights into the molecular mechanisms by which polymorphic early-stage Aß1-42 dimers have distinct impacts on DOPC membrane.

Assessments of the Effect of Neurokinin B on Toxic Aß Aggregates in Alzheimer's Disease with the Molecular Mechanisms' Action.

Clinical trials of past and current treatments for Alzheimer's disease (AD) patients on the market suffer from the dual drawbacks of a lack of efficacy and side effects. Neuropeptides have been highlighted by their potential to protect cells against AD and can reverse the toxic effect induced by Aß in cultured neurons. One of the neuropeptides that has insufficient attention in the literature as a potential treatment for prevention of the progression of AD is neurokinin B (NKB). There are critical and unresolved questions concerning the activation, and the molecular mechanisms underlying NKB effect on prevention of Aß aggregation remain unknown. The current work identifies for the first time the specific interactions that contribute to the inhibition and prevention of initial seeding of polymorphic early-stage dimers. Three main conclusions are observed in this work. First, NKB inhibits formation of polymorphic early-stage fibrillar Aß dimers. The efficiency of the inhibition depends on the concentration of NKB (i.e., NKB:Aß ratio). Second, NKB has an excellent effect of preventing the formation of initial seeding of early-stage nonfibrillar Aß dimers. Third, NKB peptides may self-assemble to form cross-α fibril-like structure during the inhibition activity of the polymorphic early-stage fibrillar Aß dimers but not during the prevention activity of early-stage nonfibrillar Aß dimers. The work provides crucial information for future experimental studies to approve the functional effect of NKB on inhibition and prevention of Aß polymorphic early-stage oligomers.

Distinct Primary Nucleation of Polymorphic Aß Dimers Yields to Distinguished Fibrillation Pathways.

Polymorphic Aß dimers are the smallest toxic species that play a role in the pathology of Alzheimer's disease. There is great interest in understanding the malfunctions that yield to these toxic species and in providing insights into the molecular mechanisms of the primary nucleation. Herein, we present a first work that demonstrates two distant edges states of Aß dimers. The first is the so-called "random coil" state dimer that mimics the primary seeding/nucleation that is far from a fibrillation state. The second is the "fibril-like" state dimer that is structurally in close proximity to the fibril, a well-organized state into a fibril-like structure. We show for the first time that a conformational change of one monomer within the dimer impedes primary nucleation, while less fluctuations and relatively large number of interactions in nucleation domains induce the primary nucleation to produce toxic stable species. Overall, the current study exhibits a diversity of primary nucleation in each dimer state, suggesting distinct molecular mechanisms of fibril formation. The conformations of the early stage Aß dimers that were achieved may provide crucial data for designing inhibitors to impede the primary nucleation.

The Role of the Anesthesiologist during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor: A Single-Center Experience.

Ablative incisionless neurosurgery has become possible through advances in focused ultrasound and magnetic resonance imaging (MRI). The great advantage of MRI-guided focused ultrasound (MRgFUS) is that the ablation is performed through an intact skull without surgery. Here, we review the new modality of MRgFUS for treating tremor and enlighten the role of the anesthesiologist in the unique procedural setting of the MRI suite. During the MRgFUS process, the patients should be awake and are required to cooperate with the medical staff to allow assessment of tremor reduction and potential occurrence of adverse effects. In addition, the patient's head is immobilized inside the MRI tunnel for hours. This combination presents major challenges for the attending anesthesiologist, who is required to try to prevent pain and nausea and when present, to treat these symptoms. Anxiety, vertigo, and vomiting may occur during treatment and require urgent treatment. Here, we review the literature available on anesthetic management during the procedure and our own experience and provide recommendations based on our collected knowledge.

Molecular mechanisms of membrane-associated amyloid aggregation: Computational perspective and challenges.

Amyloidogenic proteins are related to a variety of amyloid diseases, such as type 2 diabetes (T2D), Alzheimer's disease (AD) and Parkinson's disease (PD). The amyloid proteins in which this review focuses include amylin, Aß, tau and α-synuclein. Understanding the molecular mechanisms in which these amyloidogenic proteins interact with membranes is a challenging research to both experimental and computational studies. This review illustrates recent studies on amyloid-membrane interactions, but it mainly focuses on the challenge issues related to experimental techniques to investigate at the molecular level these interactions and provides thoughts and outlook for future computational studies.

Aromatherapy for the Treatment of Patients with Behavioral and Psychological Symptoms of Dementia: A Descriptive Analysis of RCTs.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are a common problem among patients with dementia. This problem is usually treated by drugs, but they have limited efficacy and often cause adverse effects. Aromatherapy is a nonpharmacologic treatment that is simple to use and devoid of significant adverse effects. OBJECTIVES: To review the literature on the effectiveness of aromatherapy treatment in patients with BPSD. DESIGN: A descriptive analysis of randomized clinical trials (RCTs) published in the English-language literature and cited in PubMed. RESULTS: Eleven articles on RCTs were found, of which 1 had fewer than 10 participants, 2 were mistakenly presented as RCTs, and another did not report treatment for BPSD. In all, 7 articles with 417 participants total (range, 15-114) were reviewed. The mean age in all studies was greater than 69 years (range, 69-85 years), and the percentage of women was 55% (range, 50%-57%). The intervention period ranged from 10 days to 12 weeks. Two studies used Melissa oil and 5 others used lavender oil. The studies described different methods of administration for the oils, including spraying and rubbing over various body organs. The duration of treatment differed among the studies. In 3 studies the investigators concluded that the treatment was not effective and in 3 that it was effective; in 1 study no clear conclusion could be drawn. CONCLUSIONS: The difference between positive and negative studies was not explained by differences in the study population, the type of oil, or the duration of treatment. The significant difference apparently stems from the method of administration. When the oil was applied close to the olfactory system the outcome was positive. A study should be designed to assess the effect of the site of application of aromatherapy.

Comparison of Rhabdomyolysis Markers in Patients Undergoing Bariatric Surgery with Propofol and Inhalation-based Anesthesia.

BACKGROUND: Rhabdomyolysis is a relatively uncommon, severe complication of anesthesia and surgery in the morbidly obese. As the use of propofol-based anesthesia has been associated with an increased risk of rhabdomyolysis and metabolic acidosis, this pilot study was designed to assess the effect of propofol anesthesia on the incidence of rhabdomyolysis in morbidly obese patients undergoing bariatric surgery. METHODS: Thirty, morbidly obese patients (body mass index 43 ± 3 kg/m(2)) scheduled for bariatric laparoscopic sleeve gastrectomy were randomized to receive either propofol (P) or inhalational anesthetic (I)-based balanced general anesthesia. A sample of venous blood gas analysis including pH, bicarbonate concentrations, and calculated base excess was taken at the end of the operation. Creatine phosphokinase (CPK), troponin I, blood urea nitrogen, and creatinine plasma concentrations were measured at the end of the surgery and again 24 h later. RESULTS: All patients enrolled to the study completed it without significant complications. CPK, troponin I, blood urea nitrogen, and creatinine plasma concentrations at the end of the operation and at 24 h, as well as the bicarbonate concentration and the base excess at the end of the operation were not significantly different between the two study groups. A statistically significant mild respiratory acidosis was noted in the inhalational anesthetic group (pH 7.30 ± 0.04 vs. 7.36 ± 0.02 in the propofol group) CONCLUSIONS: This small-size pilot study may suggest that propofol-based anesthesia is not related to increased incidence of rhabdomyolysis in morbidly obese patients undergoing short, uncomplicated bariatric surgery.