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Aggregation of initially stably structured proteins is involved in more than 20 human amyloid diseases. Despite intense research, however, how this class of proteins assembles into amyloid fibrils remains poorly understood, principally because of the complex effects of amino acid substitutions on protein stability, solubility, and aggregation propensity. We address this question using β2-microglobulin (β2m) as a model system, focusing on D76N-β2m that is involved in hereditary amyloidosis. This amino acid substitution causes the aggregation-resilient wild-type protein to become highly aggregation prone in vitro, although the mechanism by which this occurs remained elusive. Here, we identify the residues key to protecting β2m from aggregation by coupling aggregation with antibiotic resistance in E. coli using a tripartite β-lactamase assay (TPBLA). By performing saturation mutagenesis at three different sites (D53X-, D76X-, and D98X-β2m) we show that residue 76 has a unique ability to drive β2m aggregation in vivo and in vitro. Using a randomly mutated D76N-β2m variant library, we show that all of the mutations found to improve protein behavior involve residues in a single aggregation-prone region (APR) (residues 60 to 66). Surprisingly, no correlation was found between protein stability and protein aggregation rate or yield, with several mutations in the APR decreasing aggregation without affecting stability. Together, the results demonstrate the power of the TPBLA to develop proteins that are resilient to aggregation and suggest a model for D76N-β2m aggregation involving the formation of long-range couplings between the APR and Asn76 in a nonnative state. [ABSTRACT FROM AUTHOR]

When a SN-OD was involved, consent rates were 74% for DBD and 67% for DCD, compared with clinician-only conversations with consent rates of 52% for DBD and 29% for DCD. It is reasonable to ponder whether clinician-only conversations represent a sufficient quality experience for potential donor families. Keywords: donation after brain death; donation after circulatory death; organ donation; transplantation EN donation after brain death donation after circulatory death organ donation transplantation 1567 1571 5 11/08/21 20211201 NES 211201 The UK has seen a remarkable improvement in access to transplantation for people with end-stage organ failure following initiatives arising from the 2008 Organ Donation Taskforce report [1]. [Extracted from the article]

We present the design, simulation, and planned fabrication process of a flat high resistivity silicon gradient index (GRIN) lens for millimeter and submillimeter wavelengths with very low absorption losses. The gradient index is created by sub wavelength holes whose size increases with the radius of the lens. The effective refractive index created by the subwavelength holes is constant over a very wide bandwidth, allowing the fabrication of achromatic lenses up to submillimeter wavelengths. The designed GRIN lens was successfully simulated and shows an expected efficiency better than that of a classic silicon plano-concave spherical lens with approximately the same thickness and focal length. Deep reactive ion etching (DRIE) and wafer-bonding of several patterned wafers will be used to realize our first GRIN lens prototype. [ABSTRACT FROM AUTHOR]

Background The epidemiology of in-hospital cardiac arrests ( IHCA) in Australia and New Zealand ( ANZ) has not been systematically assessed. Aim To conduct a systematic review of the frequency, characteristics and outcomes of adult IHCA in ANZ. Methods Medline search for studies published in 1964-2014 using MeSH terms 'arrest AND hospital AND Australia', 'arrest AND hospital AND New Zealand', 'inpatient AND arrest AND Australia' and 'inpatient AND arrest AND New Zealand'. Results We screened 934 studies, analysed 50 and included 30. Frequency of IHCA ranged from 1.31 to 6.11 per 1000 admissions in 4 population studies and 0.58 to 4.59 per 1000 in 16 cohort studies. The frequency was 4.11 versus 1.32 per 1000 admissions in hospitals with rapid response system ( RRS) compared with those without ( odds ratio: 0.32; 95% confidence interval 0.28-0.37; P < 0.001). On aggregate, the initial cardiac rhythm was ventricular tachycardia/fibrillation in 31.4% (range 19.0-48.8%) in 10 studies reporting such data. On aggregate, IHCA were witnessed in 80.2% cases (three studies) and monitored patients in 53.4% cases (four studies). Details of life support were poorly documented. On aggregate, return of spontaneous circulation occurred in 46.0% of patients. Overall, 74.6% (range 59.4-77.5%) died in-hospital but survival was higher among monitored or younger patients, in those with a shockable rhythm, or during working hours. Conclusion IHCA are uncommon in ANZ and three quarters die in-hospital. However, their frequency varies markedly across institutions and may be affected by the presence of RRS. Where reported, the long-term outcomes survivors appear to have acceptable neurological outcomes. [ABSTRACT FROM AUTHOR]

We aimed to describe the experiences of families of potential organ and tissue donors eligible for donation after circulatory death or brain death. Forty-nine family members of potential donors from four Melbourne hospitals were interviewed to assess their experiences of communication, processes and the outcomes of donation. Interviews were recorded, transcribed verbatim and analysed thematically. Families expressed a range of perspectives on themes of communication, hospital processes and care, the processes of consent and donation and reflected on decisions and outcomes. They expressed satisfaction overall with communication when receiving bad news, discussing death and donation. Honest and frank communication and being kept up-to-date and prepared for potential outcomes were important aspects for families, especially those of post circulatory death donors. Participants reported high levels of trust in healthcare professionals and satisfaction with the level of care received. Many donor families indicated the process was lengthy and stressful, but not significantly enough to adversely affect their satisfaction with the outcome. Both the decision itself and knowing others' lives had been saved provided them with consolation. No consenting families, and only some non-consenting families, regretted their decisions. Many expressed they would benefit from a follow-up opportunity to ask questions and clarify possible misunderstandings. Overall, while experiences varied, Australian families valued frank communication, trusted health professionals, were satisfied with the care their family member received and with donation processes, despite some apparent difficulties. Family satisfaction, infrequently assessed, is an important outcome and these findings may assist education for Australian organ donation professionals. [ABSTRACT FROM AUTHOR]

Platypnoea-orthodeoxia syndrome has the pathognomonic clinical findings of dyspnoea and arterial hypoxaemia relieved by recumbency. We report on a patient who presented with platypnoea-orthodeoxia syndrome post laparoscopic surgery. Platypnoea-orthodeoxia syndrome is an important diagnosis to consider when investigating hypoxia without an obvious cause. [ABSTRACT FROM AUTHOR]

ObjectiveNutritionists in the UK are at the start of an exciting time of professional development. The establishment of the Association for Nutrition in 2010 has presented an opportunity to review, revitalize and expand the UK Voluntary Register of Nutritionists. In the UK and elsewhere, there is a need for a specialist register of nutritionists with title protection as a public safeguard.DesignThe new structure will base professional registration on demonstration of knowledge and application in five core competencies. Initially, there will be five specialist areas: animal; public health; nutritional scientist; food; sports and exercise. The wording and requirements linking the specialist areas to the competencies have been carefully defined by leading individuals currently on the existing register in these specialist areas. These have been evaluated by a random sample of existing registrants to check for accuracy of definitions and examples. Other work aims to establish a clear quality assurance framework in nutrition for workers in the health and social care sectors (UK Public Health Skills and Career Framework Levels 1–4) who contribute to nutrition activity, such as community food workers, nutrition assistants and pharmacists. Students, co-professional affiliates and senior fellows will also find a place in the new Association. The title ‘nutritionist’ is not currently legally protected in the UK and it is used freely to cover a range of unregulated practice.ConclusionsThe establishment of a professional register to protect the public and to provide a clear identity for nutritionists is a vital step forward. [ABSTRACT FROM PUBLISHER]

For submillimeter astronomy, particularly at 200 μm, the ARENA working group has proposed a 25m telescope at the Concordia station on Dome C. Issues related to this suggestion are reviewed. [ABSTRACT FROM AUTHOR]

To date, there have been few studies of emotion processing in those suffering from Alzheimer's disease, yet this may have an important effect on the quality of life of both sufferers and their families. This paper describes an investigation of the relative changes in cognition and in recognition and identification of non-verbal communicative signals of emotion in those suffering from Alzheimer's disease, and seeks to address the implications for clinical practice. Twelve adults with a diagnosis of `probable' Alzheimer's disease and 12 matched older adult healthy comparison participants undertook a series of tasks involving face and prosody discrimination. Facial stimuli were presented on cards, and prosodic stimuli on audiotape. Scores were compared with a measure of general cognitive ability. There was a significant difference between the Alzheimer's disease group and healthy older adult group on emotion and cognition tasks respectively. However, the ability to recognize and identify non-verbal affect cues in emotional facial expression and emotional prosody was preserved relative to general cognitive ability in those suffering from Alzheimer's disease. In addition, there were no differences found in the recognition of different emotions (happiness, sadness, anger, fear or neutral). This relative sparing of non-verbal emotional processing skills has implications for provision of assessment and interventions based on the creation of effective forms of communication that are less reliant on cognitive ability. [ABSTRACT FROM AUTHOR]

Myofascial pain is frequently overlooked in dealing with headache pain. Myofascial pain is defined as pain and/or autonomic phenomena referred from active trigger points, with associated dysfunction. The trigger point is a focus of hyperirritability in the muscle, that when compressed, is locally tender, and if sensitized, gives rise to referred pain and tenderness. The therapy for myofascial pain requires enhancing central inhibition through pharmacology or behavioral techniques and simultaneously reducing peripheral inputs through physical therapies including exercises and trigger point-specific therapy. [ABSTRACT FROM AUTHOR]

Amphotericin B has been the standard therapy for invasive aspergillosis since its introduction in 1957. It is only moderately effective. Many susceptibility tests have been used but little variation has been noted between strains. We have studied three strains of Aspergillus fumigatusand one of Aspergillus terreusin a neutropenic mouse model of invasive aspergillosis and attempted to correlate the variable efficacy in vivowith MICs generated by over 30 different susceptibility test formats. One strain of A. fumigatus(AF65) and the strain of A. terreus(AT49) were ‘resistant’ and the remaining two strains of A. fumigatus(AF210 and AF294) were ‘susceptible’ in vivo. Only AT49 had elevated MICs of amphotericin (MIC 2 mg/L) by 41 of 54 in vitrotesting systems. With each test format, including Etest, there was no distinction between MICs obtained for AF65, AF210 and AF294 (MICs 0.125–64 mg/L depending on the test). Thus despite extensive efforts we have been unable to correlate susceptible test results with in vivooutcome in A. fumigatusbut we have with A. terreus, with some test formats. This suggests that, at present, amphotericin B susceptibility testing of A. fumigatus is of limited clinical value and further work needs to be done to find testing systems that can identify the ‘resistance’ documented in vivo. [ABSTRACT FROM PUBLISHER]

Given the increased choice of therapeutic agents and the rising incidence of serious invasive disease, it is important that reliable in-vitro methods for detecting antifungal drug resistance in Aspergillus spp. are developed. Six clinical isolates of Aspergillus fumigatus, obtained from patients in whom the clinical outcome was known, were selected for study. Each was used to examine a range of parameters affecting agar dilution and broth microdilution susceptibility test results. The in-vitro results were compared with outcome in a neutropenic mouse model of invasive aspergillosis. Groups of animals were treated with itraconazole at 25 mg/kg and 75 mg/kg and survival rates and organ burdens were determined. Itraconazole was efficacious against four isolates (susceptible) but failed for two (resistant) in the animal model of infection. Both the resistant isolates had been obtained from patients receiving itraconazole treatment with good serum concentrations of the drug. Conditions for the agar dilution test which produced results that correlated best with our in-vivo observations included the use of RPMI agar with L-glutamine buffered to pH 7 with MOPS, inoculated with 10(6)-10(7) conidia/mL and incubated for 48-72 h at 28 or 35 degrees C with a no-growth endpoint. Optimal conditions for the broth microdilution method included the use of RPMI medium with L-glutamine and 2% glucose buffered to pH 7 with MOPS, an inoculum of 2 x 10(5) conidia in 200 microL incubated for 48 h at 35 degrees C with a growth (or trace) endpoint. The MICs for the susceptible isolates were 0.12-1.0 mg/L and > or = 16 mg/L for the resistant isolates. With careful selection and standardization of test conditions it is possible to generate reproducible in-vitro susceptibility data for Aspergillus spp. that will predict clinical outcome. [ABSTRACT FROM AUTHOR]

The methods currently in use for the detection and quantitation of complement activation products are slow and time consuming. We describe a method utilising immunofixation after agarose or cellulose acetate membrane electrophoresis which allows large batches of samples to be screened rapidly for the presence of activation products of C3 and factor B. Further, after immunofixation on agarose the conversion product may be quantitated by densitometry. This method gives similar results to those obtained by crossed immunoelectrophoresis. Using both this technique and crossed immunoelectrophoresis we have been able to confirm that C4 activation occurs during electrophoresis in the absence of EDTA and that in the presence of EDTA it is not demonstrable even in patients with active immune complex disease. [ABSTRACT FROM PUBLISHER]