How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism.

Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's dis-ease (AD). Previously we found that in vitro the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disas-sembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find as-sembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by the disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases.

How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism.

Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's disease (AD). Previously we found that in vitro the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disassembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find assembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases.

The efficacy of a chinstrap in treating sleep disordered breathing and snoring.

STUDY OBJECTIVES: A previously published case report suggested that a chinstrap alone might improve obstructive sleep apnea (OSA). We conducted this study to determine whether a chinstrap was a feasible alternative to continuous positive airway pressure (CPAP) in patients with OSA. METHODS: 26 adult patients with OSA (apnea-hypopnea index [AHI] > 5/h on diagnostic polysomnogram [PSG]) underwent a modified split-night PSG, using only a chinstrap for the first 2 hours of sleep, followed by CPAP titration for the remainder of the night. Improvements in AHI, arterial oxygen saturation (SpO2), and snoring with chinstrap use were compared to results with optimal CPAP pressures. RESULTS: There was no significant difference between the diagnostic PSG and the chinstrap portion of the split-night PSG in the following parameters: general AHI (median [IQR] 16.0/h [9.7-26.0] vs. 25.9/h [10.7-42.7]), SpO2 nadir (84.0% [80.5-87.5] vs. 87.0 [84.0-88.5]), AHI in REM sleep (26.7/h [16.8-43.7] vs. 42.4/h [21.3-57.7]), AHI in supine sleep (24.9/h [11.9-51.5] vs. 29.8/h [11.7-55.5]), snoring index (253.2/h [147.5-353.1] vs. 180.0/h [9.8-393.3]) or subjective snoring scale (3.0 [0.8-3.0] vs. 2.5 [0.4-3.0]). The AHI and SpO2 nadir in the 13 patients with mild OSA also did not improve with chinstrap use (9.6/h [8.1-12.2] vs. 10.6/h [6.8-35.4] and 87.0% [83.0-90.0] vs. 88.0% [87.0-89.0]). All these parameters showed significant improvement with optimal CPAP titration (p < 0.05). CONCLUSIONS: A chinstrap alone is not an effective treatment for OSA. It does not improve sleep disordered breathing, even in mild OSA, nor does it improve the AHI in REM sleep or supine sleep. It is also ineffective in improving snoring.

CT scanning in the evaluation of pulmonary hypertension.

BACKGROUND: Right-heart catheterization is currently the gold standard method for detecting pulmonary hypertension (PH) and grading its severity. Our study determined the utility of computerized tomography (CT) scans for detecting PH in patients with left-sided heart disease, thereby potentially avoiding the overuse of invasive right-heart catheterization. METHODS: A retrospective review was conducted on 40 patients with left-sided cardiac pathology who had undergone both right-heart catheterization and CT scanning of the chest. Mean pulmonary artery diameters (MPADs) were measured on CT scans and compared with pulmonary artery pressures measured by right-heart catheterization. RESULTS: Patients with mild-to-moderate PH had significantly greater CT-measured MPADs (34.89 ± 1.01) than patients without PH (controls) (27.36 ± 0.83, p < 0.001). Patients with severe PH had significantly greater MPADs (38.31 ± 0.88) than both mild-to-moderate PH patients (p < 0.01) and controls (p < 0.001). Receiver operating characteristic curve analysis showed that CT scanning predicted PH with an area under the curve of 0.95 (p < 0.0001). A cutoff MPAD of >33.3 mm had 100% specificity and 100% positive predictive value (N = 40, p < 0.0001), and a cutoff MPAD of <27.3 mm had 100% sensitivity with 100% negative predictive value (N = 40, p < 0.001). CONCLUSIONS: CT scanning correctly identified all patients with PH with MPADs >34 mm and excluded all patients without PH when MPADs were <27 mm. We advocate that the measurement of MPAD by CT scanning can be quickly and easily performed by the clinician to screen for the presence of PH.

Hepatic hydrothorax without any evidence of ascites.

Hepatic hydrothorax usually presents in association with ascites, but there are rare cases when it does not. This case helps to support the differential of hepatic hydrothorax in patients who have a history of liver cirrhosis, portal hypertension, and recurrent pleural effusions without ascites. We hope to support the conclusion that a patient with recurrent pleural effusions, without ascites, does not exclude gastrointestinal involvement in its etiology.

Mounier-Kuhn syndrome: a case report.

Mounier-Kuhn syndrome is a rare clinical entity. It was described in 1932 to refer to the presence of tracheobronchomegaly. The clinical presentation is variable and it can occur in several different age groups. We present the case of a young man who was admitted to the hospital for an asthma exacerbation and was found to have tracheobronchomegaly on his CT scan. A review of the literature for this rare, but interesting, phenomenon is included.