The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein

Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP^Sc) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel prion intervention by the polyphenolic phytoalexin, polydatin which binds with moderate affinity to the recombinant protease resistant core of human prion protein, encompassing the sequence 90–231 (rPrP^res) and inhibits its conversion into the highly neurotoxic forms. An extensive evaluation using biophysical techniques revealed that polydatin incubated rPrP^res samples generate off-pathway oligomers having reduced cross-β sheet signature, and relatively smaller in size than the native rPrP^res oligomers. The detailed structural analysis using molecular dynamics simulations elucidated the induction of antagonistic mobilities in the β2–α2 loop, α3 helix and the N-terminal amyloidogenic region of prions. This study puts forward novel prion fibrillogenesis inhibitory potential of polydatin, specifically by stabilizing the N-terminal amyloidogenic region. Collectively our results affirm the importance of polydatin in crippling the prion pathogenesis and may serve as a structural scaffold for designing novel therapeutic agents targeting amyloidogenic transition in prions.

Polydatin is found to be a pharmacologically-significant scaffold that can bind to the rPrP^res repertoire and inhibit its conversion to the highly infectious and neurotoxic PrP^Sc-like form, thus acting like a promising anti-prion drug lead.     

Phoenixin influences the excitability of nucleus of the solitary tract neurones,effects which are modified by environmental and glucocorticoid stress

Phoenixin (PNX) is a neuropeptide shown to play roles in the control of reproduction. The nucleus of the solitary tract (NTS), a critical autonomic integrating centre in the hindbrain, is one of many areas with dense expression of PNX. Using coronal NTS slices obtained from male Sprague‐Dawley rats, the present study characterised the effects of PNX on both spike frequency and membrane potential of NTS neurones. Extracellular recordings demonstrated that bath‐applied 10 nmol L^‐1 PNX increased the firing frequency in 32% of NTS neurones, effects which were confirmed with patch‐clamp recordings showing that 50% of NTS neurones tested depolarised in response to application of the peptide. Surprisingly, the responsiveness to PNX in NTS neurones then declined suddenly to 9% (P < 0.001). This effect was subsequently attributed to stress associated with construction in our animal care facility because PNX responsiveness was again observed in slices from rats delivered and maintained in a construction‐free facility. We then examined whether this loss of PNX responsiveness could be replicated in rats placed on a chronic stress regimen involving ongoing corticosterone (CORT) treatment in the construction‐free facility. Slices from animals treated in this way showed a similar lack of neuronal responsiveness to PNX (9.1 ± 3.9%) within 2 weeks of CORT treatment. These effects were specific to PNX responsiveness because CORT treatment had no effect on the responsiveness of NTS neurones to angiotensin II. These results are the first to implicate PNX with respect to directly controlling the excitability of NTS neurones and also provide intriguing data showing the plasticity of these effects associated with environmental and glucocorticoid stress levels of the animal.     

Changes in gastro-intestinal function in humans at an altitude of 3,500 m

Summary The gastric juice secretion, acid concentration and peptic activity were studied before and after pentagastrin stimulation in 10 sea level residents, first at sea level and then during 22 days sojourn at 3,500 m and in two other groups of 10 men, one of which consisted of natives of high altitude and the other of lowlanders acclimatized to high altitude. In addition, measurements of xylose excretion, energy, fat and protein utilization, along with fluid balance were made on sea level residents, referred to as sojourners, both at sea level and high altitude.The basal and maximal gastric juice volumes of the three groups at high altitude did not differ significantly. The maximal rate of acid production was lower in high altitude natives as compared to the other two groups. Peptic activity was higher in sojourners at high altitude, whereas it did not show any difference in acclimatised low landers as compared to sea level values of sojourners. There was no significant difference in D-xylose excretion in sojourners at high altitude. The food intake of sojourners was reduced at high altitude without any change in the efficiency of food utilization. There was no change in fluid balance.     

Report of the Ad Hoc Committee on Risk Factors for Coronary Artery Bypass Surgery

The Society of Thoracic Surgeons remains greatly concerned about the use of raw mortality data as the sole measure to determine quality of care following coronary artery bypass surgery. Use of such data without consideration of risk factors that are predictors of hospital mortality and of other indices of quality of care is inappropriate and misleading and may adversely affect the care of the high-risk cardiac surgical patient. The Society is committed to the principle of providing the public with accurate information regarding the conduct of coronary artery surgery. However, it believes that the data provided by HCFA do not provide this information and should not be used as the sole index of quality of care following coronary artery bypass surgery.     

Post‐Traumatic Heterotopic Ossification: An Old Problem in Need of New Solutions

Heterotopic ossification (HO) is the formation of pathological bone in ectopic sites and it can have serious consequences for functional outcomes. For many years, its main clinical relevance was as a rare complication of elective joint arthroplasty or CNS injury and a number of prophylaxes were developed to mitigate against it in these settings. As a consequence of changes in patterns of wounding and survival in conflicts since the turn of the century, post‐traumatic HO has become much more common and case severity has increased. It represents one of the main barriers to rehabilitation in a large cohort of combat‐injured patients. However, extant prophylaxes have not been shown to be effective or appropriate in this patient cohort. In addition, the lack of reliable early detection or means of predicting which patients will develop HO is another barrier to effective prevention. This review examines the current state of understanding of post‐traumatic HO including the historical context, epidemiology, pathophysiology, clinical issues, currently prophylaxis and detection, management, and potential future approaches. Our aims are to highlight the current lack of effective means of early detection and prevention of HO after major trauma and to stimulate research into novel solutions to this challenging problem. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1061–1068, 2018.