Polar zipper sequence in the high-affinity hemoglobin of Ascaris suum: amino acid sequence and structural interpretation.

The extracellular hemoglobin of Ascaris has an extremely high oxygen affinity (P50 = 0.004 mmHg). It consists of eight identical subunits of molecular weight 40,600. Their sequence, determined by protein chemistry, shows two tandemly linked globin-like sequences and an 18-residue C-terminal extension. Two N-linked glycosylation sites contain equal ratios of mannose/glucosamine/fucose of 3:2:1. Electron micrographs suggest that the eight subunits form a polyhedron of point symmetry D4, or 42. The C-terminal extension contains a repeat of the sequence Glu-Glu-His-Lys, which would form a pattern of alternate glutamate and histidine side chains on one side and of glutamate and lysine side chains on the other side of a beta strand. We propose that this represents a polar zipper sequence and that the C-terminal extensions are joined in an eight-stranded beta barrel at the center of the molecule, with histidine and glutamate side chains inside and lysine and glutamate side chains outside the barrel compensating each other's charges. The amino acid sequence of Ascaris hemoglobin fails to explain its high oxygen affinity.     

Patients with treated indolent lymphomas immunized with BNT162b2 have reduced anti-spike neutralizing IgG to SARS-CoV-2 variants,but preserved antigen-specific T cell responses

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN (N = 9), ICT (N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti-spike immunoglobulin G (IgG) was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti-spike IgG correlated with lymphocyte count (r = .63; p = .002), and time from treatment (r = .56; p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis (p = .03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC (p < .0001). Anti-spike IgG correlated with neutralization of the delta variant (r = .62, p < .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p < .0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant.     

The relation between blood pressure changes induced by passive leg raising and arterial stiffness

Passive leg raising (PLR) elicits cardiorespiratory changes because of intra-thoracic blood pooling. We previously found PLR to lower blood pressure (BP) in healthy subjects. To determine the effects of cardiovascular (CV) risk factors on the PLR BP lowering response, we measured brachial artery, systolic (SBP), diastolic (DBP), and pulse pressure (PP) before and 1 minute after 60° PLR, in 125 subjects (58% males, age 48 ± 18 years) with/without CV risk factors/disease. Baseline carotid-radial pulse wave velocity (PWV) and augmentation index (AI) were measured by applanation tonometry. Changes (?) in SBP and BA PP ranged from +31 to –27 and +35 to –20 mm Hg and were normally distributed. Mean BP decreases upon PLR were ΔSBP –3 ± 9 (P < .001), and ΔPP –2 ± 8 mm Hg (P = .04). On univariate analyses, ΔSBP was correlated with age (r = 0.31, P < .001), PWV (r = 0.53, P < .001), AI (r = 0.25, P < .01), hypertension (r = 0.37, P < .001), hypercholesterolemia (r = 0.25, P < .01) and renal insufficiency (r = 0.19, P = .038). ΔPP was correlated with age (r = 0.31, P < .001), PWV (r = 0.45, P < .001), AI (r = 0.23, P = .01), hypertension (r = 0.22, P = .01), hypercholesterolemia (r = 0.27, P < .001). Multivariate analysis showed PWV the only independent predictor of ΔSBP (B = 3.2, r² = 0.40, P < .001) and of ΔPP (B = 2.6, r² = 0.36, P < .001). Therefore, changes in SBP and PP induced by PLR are independently and inversely related to carotid-radial PWV.     

Idiopathic esophageal ulceration in acquired immunodeficiency syndrome: successful treatment with misoprostol and viscous lidocaine

Objective: Esophageal ulceration is a common and important cause of morbidity in patients with acquired immunodeficiency syndrome (AIDS). After known causes are excluded, a subgroup remains with unexplained esophageal ulceration, known as idiopathic esophageal ulceration (IEU). The current therapy of IEU includes corticosteroids or, less frequently, thalidomide, although no placebo-controlled trials have been reported. The aim of this retrospective study was to determine the outcome of treating IEU with misoprostol and viscous lidocaine.
Methods: A retrospective review of esophageal ulceration in AIDS identified seven subjects with IEU at our institution. IEU in these subjects was treated successfully with misoprostol, 200 μg, crushed and suspended in 2% viscous lidocaine, 15 ml, given orally a.c. and h.s. for 4 wk.
Results: All patients reported symptomatic improvement within 2–3 days and complete resolution of their symptoms within 15 days. Healing of esophageal ulcerations was confirmed in five of seven subjects at a repeat endoscopy 8–12 wk later.
Conclusions: Misoprostol, an antiulcer drug, has GI cytoprotective properties, and viscous lidocaine, a topical anesthetic, coats mucosal surfaces. We speculate that misoprostol when delivered topically is 3–6 times more effective than when delivered systemically. Considering the rapid resolution of symptoms, healing of ulcers, and lack of side effects, we believe that misoprostol crushed and suspended in viscous lidocaine should be considered for further evaluation in prospective, placebo-controlled trials of IEU.