The three-dimensional structure of human serum albumin has been solved at 6.0 angstrom (Å) resolution by the method of multiple isomorphous replacement. Crystals were grown from solutions of polyethylene glycol in the infrequently observed space group P 42 1 2 (unit cell constants a = b = 186.5 ± 0.5 Å and c = 81.0 ± 0.5 Å) and diffracted x-rays to lattice d -spacings of less than 2.9 A. The electron density maps are of high quality and revealed the structure as a predominantly α-helical globin protein in which the course of the polypeptide can be traced. The binding loci of several organic compounds have been determined.

The mechanism by which tumor necrosis factor-␣ (TNF) differentially modulates type I diabetes mellitus in the nonobese diabetic (NOD) mouse is not well understood. CD4 ؉ CD25 ؉ T cells have been implicated as mediators of self-tolerance. We show (i) NOD mice have a relative deficiency of CD4 ؉ CD25 ؉ T cells in thymus and spleen; (ii) administration of TNF or anti-TNF to NOD mice can modulate levels of this population consistent with their observed differential age-dependent effects on diabetes in the NOD mouse; (iii) CD4 ؉ CD25 ؉ T cells from NOD mice treated neonatally with TNF show compromised effector function in a transfer system, whereas those treated neonatally with anti-TNF show no alteration in ability to prevent diabetes; and (iv) repeated injection of CD4 ؉ CD25 ؉ T cells into neonatal NOD mice delays diabetes onset for as long as supplementation occurred. These data suggest that alterations in the number and function of CD4 ؉ CD25 ؉ T cells may be one mechanism by which TNF and anti-TNF modulate type I diabetes mellitus in NOD mice.

PurposeCurrent guidelines recommend maintaining a mean arterial pressure (MAP) ≥ 65 mmHg in septic patients. However, the relationship between hypotension and major complications in septic patients remains unclear. We, therefore, evaluated associations of MAPs below various thresholds and in-hospital mortality, acute kidney injury (AKI), and myocardial injury.MethodsWe conducted a retrospective analysis using electronic health records from 110 US hospitals. We evaluated septic adults with intensive care unit (ICU) stays ≥ 24 h from 2010 to 2016. Patients were excluded with inadequate blood pressure recordings, poorly documented potential confounding factors, or renal or myocardial histories documented within 6 months of ICU admission. Hypotension exposure was defined by time-weighted average mean arterial pressure (TWA-MAP) and cumulative time below 55, 65, 75, and 85 mmHg thresholds. Multivariable logistic regressions determined the associations between hypotension exposure and in-hospital mortality, AKI, and myocardial injury.ResultsIn total, 8,782 patients met study criteria. For every one unit increase in TWA-MAP < 65 mmHg, the odds of in-hospital mortality increased 11.4% (95% CI 7.8%, 15.1%, p < 0.001); the odds of AKI increased 7.0% (4.7, 9.5%, p < 0.001); and the odds of myocardial injury increased 4.5% (0.4, 8.7%, p = 0.03). For mortality and AKI, odds progressively increased as thresholds decreased from 85 to 55 mmHg.ConclusionsRisks for mortality, AKI, and myocardial injury were apparent at 85 mmHg, and for mortality and AKI risk progressively worsened at lower thresholds. Maintaining MAP well above 65 mmHg may be prudent in septic ICU patients.Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5218-5) contains supplementary material, which is available to authorized users.

PurposeRecent data suggest that both elevated serum chloride levels and volume overload may be harmful during fluid resuscitation. The purpose of this study was to examine the relationship between the intravenous chloride load and in-hospital mortality among patients with systemic inflammatory response syndrome (SIRS), with and without adjustment for the crystalloid volume administered.MethodsWe conducted a retrospective analysis of 109,836 patients ≥18 years old that met criteria for SIRS and received fluid resuscitation with crystalloids. We examined the association between changes in serum chloride concentration, the administered chloride load and fluid volume, and the ‘volume-adjusted chloride load’ and in-hospital mortality.ResultsIn general, increases in the serum chloride concentration were associated with increased mortality. Mortality was lowest (3.7 %) among patients with minimal increases in serum chloride concentration (0–10 mmol/L) and when the total administered chloride load was low (3.5 % among patients receiving 100–200 mmol; P < 0.05 versus patients receiving ≥500 mmol). After controlling for crystalloid fluid volume, mortality was lowest (2.6 %) when the volume-adjusted chloride load was 105–115 mmol/L. With adjustment for severity of illness, the odds of mortality increased (1.094, 95 % CI 1.062, 1.127) with increasing volume-adjusted chloride load (≥105 mmol/L).ConclusionsAmong patients with SIRS, a fluid resuscitation strategy employing lower chloride loads was associated with lower in-hospital mortality. This association was independent of the total fluid volume administered and remained significant after adjustment for severity of illness, supporting the hypothesis that crystalloids with lower chloride content may be preferable for managing patients with SIRS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-014-3505-3) contains supplementary material, which is available to authorized users.

Staphylococcal enterotoxins are exotoxins produced byStaphylococcus aureus that possess emetic and superantigenic properties. Prior to this research there were six characterized enterotoxins, staphylococcal enterotoxin types A to E and H (referred to as SEA to SEE and SEH). Two new staphylococcal enterotoxin genes have been identified and designated segand sei (staphylococcal enterotoxin types G and I, respectively). seg and sei consist of 777 and 729 nucleotides, respectively, encoding precursor proteins of 258 (SEG) and 242 (SEI) deduced amino acids. SEG and SEI have typical bacterial signal sequences that are cleaved to form toxins with 233 (SEG) and 218 (SEI, predicted) amino acids, corresponding to mature proteins of 27,043 Da (SEG) and 24,928 Da (SEI). Biological activities for SEG and SEI were determined with recombinant S. aureus strains. SEG and SEI elicited emetic responses in rhesus monkeys upon nasogastric administration and stimulated murine T-cell proliferation with the concomitant production of interleukin 2 (IL-2) and gamma interferon (IFN-γ), as measured by cytokine enzyme-linked immunoassays. SEG and SEI are related to other enterotoxins of S. aureus and to streptococcal pyrogenic exotoxin A (SpeA) and streptococcal superantigen (SSA) of Streptococcus pyogenes. Phylogenetic analysis and comparisons of amino acid and nucleotide sequence identities were performed on related staphylococcal and streptococcal protein toxins to group SEG and SEI among the characterized toxins. SEG is most similar to SpeA, SEB, SEC, and SSA (38 to 42% amino acid identity), while SEI is most similar to SEA, SEE, and SED (26 to 28% amino acid identity). Polyclonal antiserum was generated against purified histidine-tagged SEG and SEI (HisSEG and HisSEI). Immunoblot analysis of the enterotoxins, toxic-shock syndrome toxin 1, and SpeA with antiserum prepared against HisSEG and HisSEI revealed that SEG shares some epitopes with SEC1 while SEI does not.

BackgroundThe utility of pulmonary artery catheters (PACs) and their measurements depend on a variety of factors including data interpretation and personnel training. This US multi-center, retrospective electronic health record (EHR) database analysis was performed to identify associations between PAC use in adult cardiac surgeries and effects on subsequent clinical outcomes.MethodsThis cohort analysis utilized the Cerner Health Facts database to examine patients undergoing isolated coronary artery bypass graft (CABG), isolated valve surgery, aortic surgery, other complex non-valvular and multi-cardiac procedures, and/or heart transplant from January 1, 2011, to June 30, 2015. A total of 6844 adults in two cohorts, each with 3422 patients who underwent a qualifying cardiac procedure with or without the use of a PAC for monitoring purposes, were included. Patients were matched 1:1 using a propensity score based upon the date and type of surgery, hospital demographics, modified European System for Cardiac Operative Risk Evaluation (EuroSCORE II), and patient characteristics. Primary outcomes of 30-day in-hospital mortality, length of stay, cardiopulmonary morbidity, and infectious morbidity were analyzed after risk adjustment for acute physiology score.ResultsThere was no difference in the 30-day in-hospital mortality rate between treatment groups (OR, 1.17; 95% CI, 0.65–2.10; p = 0.516). PAC use was associated with a decreased length of stay (9.39 days without a PAC vs. 8.56 days with PAC; p < 0.001), a decreased cardiopulmonary morbidity (OR, 0.87; 95% CI, 0.79–0.96; p < 0.001), and an increased infectious morbidity (OR, 1.28; 95% CI, 1.10–1.49; p < 0.001).ConclusionsUse of a PAC during adult cardiac surgery is associated with decreased length of stay, reduced cardiopulmonary morbidity, and increased infectious morbidity but no increase in the 30-day in-hospital mortality. This suggests an overall potential benefit associated with PAC-based monitoring in this population.Trial registrationThe study was registered at clinicaltrials.gov (NCT02964026) on November 15, 2016.Electronic supplementary materialThe online version of this article (10.1186/s13741-018-0103-x) contains supplementary material, which is available to authorized users.

To assess the role of lymphotoxin-β receptor (LTβR) in diabetes pathogenesis, we expressed an LTβR–Fc fusion protein in nonobese diabetic (NOD) mice. The fusion protein was expressed in the embryo, reached high levels for the first 2 wk after birth, and then declined progressively with age. High expression of LTβR–Fc blocked diabetes development but not insulitis. After the decline in chimeric protein concentration, mice became diabetic with kinetics similar to the controls. Early expression of fusion protein resulted in disrupted splenic architecture. However, primary follicles and follicular dendritic cells, but not marginal zones, developed in aged mice. Hence, LTβR signaling is required for diabetes development and regulates follicular and marginal zone structures via qualitatively or quantitatively distinct mechanisms.

IntroductionIntravenous (IV) fluids may be associated with complications not often attributed to fluid type. Fluids with high chloride concentrations such as 0.9 % saline have been associated with adverse outcomes in surgery and critical care. Understanding the association between fluid type and outcomes in general hospitalized patients may inform selection of fluid type in clinical practice. We sought to determine if the type of IV fluid administered to patients with systemic inflammatory response syndrome (SIRS) is associated with outcome.MethodsThis was a propensity-matched cohort study in hospitalized patients receiving at least 500 mL IV crystalloid within 48 hours of SIRS. Patient data was extracted from a large multi-hospital electronic health record database between January 1, 2009, and March 31, 2013. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, readmission, and complications measured by ICD-9 coding and clinical definitions. Outcomes were adjusted for illness severity using the Acute Physiology Score. Of the 91,069 patients meeting inclusion criteria, 89,363 (98 %) received 0.9 % saline whereas 1706 (2 %) received a calcium-free balanced solution as the primary fluid.ResultsThere were 3116 well-matched patients, 1558 in each cohort. In comparison with the calcium-free balanced cohort, the saline cohort experienced greater in-hospital mortality (3.27 % vs. 1.03 %, P <0.001), length of stay (4.87 vs. 4.38 days, P = 0.016), frequency of readmission at 60 (13.54 vs. 10.91, P = 0.025) and 90 days (16.56 vs. 12.58, P = 0.002) and frequency of cardiac, infectious, and coagulopathy complications (all P <0.002). Outcomes were defined by administrative coding and clinically were internally consistent. Patients in the saline cohort received more chloride and had electrolyte abnormalities requiring replacement more frequently (P <0.001). No differences were found in acute renal failure.ConclusionsIn this large electronic health record, the predominant use of 0.9 % saline in patients with SIRS was associated with significantly greater morbidity and mortality compared with predominant use of balanced fluids. The signal is consistent with that reported previously in perioperative and critical care patients. Given the large population of hospitalized patients receiving IV fluids, these differences may confer treatment implications and warrant corroboration via large clinical trials.Trial registrationNCT02083198 clinicaltrials.gov; March 5, 2014Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1045-z) contains supplementary material, which is available to authorized users.