A series of helical structures for gramicidin A, with alternating L and D residues, are characterized as to number of residues per turn, atoms in hydrogenbonded rings, and dihedral angles. Because of alternating peptide C-O directions, these helices are capable of forming head-to-head hydrogen-bonded dimers with the capacity of functioning as transmembrane channels. The dimers are characterized as to channel length, pore size, and expected ion selectivity.In a test of the proposed head-to-head association for channel formation, the malonyl dimer [NN'-(dideform yl gramicidin A)-malonamideJ was synthesized. The chemical and conformational integrity of the product was verified by nuclear magnetic resonance; in lipid bilayer studies, the dimer was found to be a potent mediator of ion conductance with the predicted concentration dependence.Thus, the results on malonyl gramicidin A prove headto-head association in formation of the transmembrane channel, and the results are consistent with the specific geometrical configuration involved in head-to-head dimerization of lr(L,D) helices. At this stage, the action of gramicidin A on membranes with lipid-layer thicknesses of 30 A or less can best be understood in terms of the 7r(LD) helix with 6.3 residues per turn.On the basis of the Pauling-Corey-Donohue postulates for polypeptide structure (1-4), the conformational energy diagrams for backbone dihedral angles of polypeptides (5, 6), and the characteristics of gramicidin A-mediated ion conductance across lipid bilayers (7, 8,*), coupled with the significant fact that the amino acids in this peptide are in alternating I-D sequence (9, 10), a left-handed 2r(LD) helix has been proposed for the gramicidin A transmembrane channel (11), which has the unusual property of being capable of head-to-head dimerization. The head-to-head hydrogen-bonded association of two helices is possible because the peptide C-O bonds alternate in direction, with orientations primarily parallel and antiparallel to the helix axis. In this paper we generalize the possibilities of head-to-head association of left-handed gramicidin A helices of the TK(LD) type and demonstrate, by examining the lipid bilayer activity and NMR spectrum of a derivative obtained by chemically coupling the a-amino moieties of two deformyl gramicidin A molecules (i.e., by forming the malonamide dimer), that the transmembrane channel is formed by head-to-head association.THE SET OF 7(L.D) HELICES The sequence of gramicidin A, HCO-iVal-Gly-L-Ala-Trp-D-Leu-i-Trp-NHCH2CH20H, with its alternating L and D residues, makes possible a set of helices that differ from all previously described helices in that the peptide C-O bond vectors alternate with components parallel and antiparallel to the axis of the helix. If we define the direction of the helix axis vector from the amino to the carboxyl terminus, the C-O moieties of the L residues in lr(LD) helices of gramicidin A have components parallel to this vector, whereas for the D residues, they are antiparallel to it. In the a-...
BackgroundThe NICE guideline for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) emphasises the need for an early diagnosis in primary care with management tailored to patient needs. However, GPs can be reluctant to make a diagnosis and are unsure how to manage people with the condition.MethodsA meta synthesis of published qualitative studies was conducted, producing a multi-perspective description of barriers to the diagnosis and management of CFS/ME, and the ways that some health professionals have been able to overcome them. Analysis provided second-order interpretation of the original findings and developed third-order constructs to provide recommendations for the medical curriculum.ResultsTwenty one qualitative studies were identified. The literature shows that for over 20 years health professionals have reported a limited understanding of CFS/ME. Working within the framework of the biomedical model has also led some GPs to be sceptical about the existence of the condition. GPs who provide a diagnosis tend to have a broader, multifactorial, model of the condition and more positive attitudes towards CFS/ME. These GPs collaborate with patients to reach agreement on symptom management, and use their therapeutic skills to promote self care.ConclusionsIn order to address barriers to the diagnosis and management of CFS/ME in primary care, the limitations of the biomedical model needs to be recognised. A more flexible bio-psychosocial approach is recommended where medical school training aims to equip practitioners with the skills needed to understand, support and manage patients and provide a pathway to refer for specialist input.
In a randomized trial in Malawi of azithromycin versus placebo in over 2,000 pregnant women, Jim Neilson and colleagues show no benefit of azithromycin for a number of outcomes including preterm birth and prenatal death.
Background During the COVID-19 pandemic, there have been concerns regarding potential bias in pulse oximetry measurements for people with high levels of skin pigmentation. We systematically reviewed the effects of skin pigmentation on the accuracy of oxygen saturation measurement by pulse oximetry (SpO2) compared with the gold standard SaO2 measured by CO-oximetry. Methods We searched Ovid MEDLINE, Ovid Embase, EBSCO CINAHL, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (up to December 2021) for studies with SpO2–SaO2 comparisons and measuring the impact of skin pigmentation or ethnicity on pulse oximetry accuracy. We performed meta-analyses for mean bias (the primary outcome in this review) and its standard deviations (SDs) across studies included for each subgroup of skin pigmentation and ethnicity and used these pooled mean biases and SDs to calculate accuracy root-mean-square (Arms) and 95% limits of agreement. The review was registered with the Open Science Framework (https://osf.io/gm7ty). Results We included 32 studies (6505 participants): 15 measured skin pigmentation and 22 referred to ethnicity. Compared with standard SaO2 measurement, pulse oximetry probably overestimates oxygen saturation in people with the high level of skin pigmentation (pooled mean bias 1.11%; 95% confidence interval 0.29 to 1.93%) and people described as Black/African American (1.52%; 0.95 to 2.09%) (moderate- and low-certainty evidence). The bias of pulse oximetry measurements for people with other levels of skin pigmentation or those from other ethnic groups is either more uncertain or suggests no overestimation. Whilst the extent of mean bias is small or negligible for all subgroups evaluated, the associated imprecision is unacceptably large (pooled SDs > 1%). When the extent of measurement bias and precision is considered jointly, pulse oximetry measurements for all the subgroups appear acceptably accurate (with Arms < 4%). Conclusions Pulse oximetry may overestimate oxygen saturation in people with high levels of skin pigmentation and people whose ethnicity is reported as Black/African American, compared with SaO2. The extent of overestimation may be small in hospital settings but unknown in community settings. Review protocol registration https://osf.io/gm7ty
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