Withdrawing intra-aortic balloon pump support paradoxically improves microvascular flow

Introduction: The Intra-Aortic Balloon Pump (IABP) is frequently used to mechanically support the heart. There is evidence that IABP improves microvascular flow during cardiogenic shock but its influence on the human microcirculation in patients deemed ready for discontinuing IABP support has not yet been studied. Therefore we used sidestream dark field imaging (SDF) to test our hypothesis that human microcirculation remains unaltered with or without IABP support in patients clinically ready for discontinuation of mechanical support. Methods: We studied 15 ICU patients on IABP therapy. Measurements were performed after the clinical decision was made to remove the balloon catheter. We recorded global hemodynamic parameters and performed venous oximetry during maximal IABP support (1:1) and 10 minutes after temporarily stopping the IABP therapy. At both time points, we also recorded video clips of the sublingual microcirculation. From these we determined indices of microvascular perfusion including perfused vessel density (PVD) and microvascular flow index (MFI). Results: Ceasing IABP support lowered mean arterial pressure (74 +/- 8 to 71 +/- 10 mmHg; P = 0.048) and increased diastolic pressure (43 +/- 10 to 53 +/- 9 mmHg; P = 0.0002). However, at the level of the microcirculation we found an increase of PVD of small vessels <20 mu m (5.47 +/- 1.76 to 6.63 +/- 1.90; P = 0.0039). PVD for vessels >20 mu m and MFI for both small and large vessels were unaltered. During the procedure global oxygenation parameters (ScvO(2)/SvO(2)) remained unchanged. Conclusions: In patients deemed ready for discontinuing IABP support according to current practice, SDF imaging showed an increase of microcirculatory flow of small vessels after ceasing IABP therapy. This observation may indicate that IABP impairs microvascular perfusion in recovered patients, although this warrants confirmatio

Rickettsia Phylogenomics: Unwinding the Intricacies of Obligate Intracellular Life

BACKGROUND: Completed genome sequences are rapidly increasing for Rickettsia, obligate intracellular alpha-proteobacteria responsible for various human diseases, including epidemic typhus and Rocky Mountain spotted fever. In light of phylogeny, the establishment of orthologous groups (OGs) of open reading frames (ORFs) will distinguish the core rickettsial genes and other group specific genes (class 1 OGs or C1OGs) from those distributed indiscriminately throughout the rickettsial tree (class 2 OG or C2OGs). METHODOLOGY/PRINCIPAL FINDINGS: We present 1823 representative (no gene duplications) and 259 non-representative (at least one gene duplication) rickettsial OGs. While the highly reductive (approximately 1.2 MB) Rickettsia genomes range in predicted ORFs from 872 to 1512, a core of 752 OGs was identified, depicting the essential Rickettsia genes. Unsurprisingly, this core lacks many metabolic genes, reflecting the dependence on host resources for growth and survival. Additionally, we bolster our recent reclassification of Rickettsia by identifying OGs that define the AG (ancestral group), TG (typhus group), TRG (transitional group), and SFG (spotted fever group) rickettsiae. OGs for insect-associated species, tick-associated species and species that harbor plasmids were also predicted. Through superimposition of all OGs over robust phylogeny estimation, we discern between C1OGs and C2OGs, the latter depicting genes either decaying from the conserved C1OGs or acquired laterally. Finally, scrutiny of non-representative OGs revealed high levels of split genes versus gene duplications, with both phenomena confounding gene orthology assignment. Interestingly, non-representative OGs, as well as OGs comprised of several gene families typically involved in microbial pathogenicity and/or the acquisition of virulence factors, fall predominantly within C2OG distributions. CONCLUSION/SIGNIFICANCE: Collectively, we determined the relative conservation and distribution of 14354 predicted ORFs from 10 rickettsial genomes across robust phylogeny estimation. The data, available at PATRIC (PathoSystems Resource Integration Center), provide novel information for unwinding the intricacies associated with Rickettsia pathogenesis, expanding the range of potential diagnostic, vaccine and therapeutic targets

Vitamin B-6 vitamers in human plasma and cerebrospinal fluid

BACKGROUND: Vitamin B-6 comprises a group of 6 interrelated vitamers and is essential for numerous physiologic processes, including brain functioning. Genetic disorders disrupting vitamin B-6 metabolism have severe clinical consequences. OBJECTIVE: To adequately diagnose known and novel disorders in vitamin B-6 metabolism, a reference set is required containing information on all vitamin B-6 vitamers in plasma and cerebrospinal fluid (CSF). DESIGN: Concentrations of vitamin B-6 vitamers in the plasma and CSF of 533 adult subjects were measured by ultra high-performance liquid chromatography-tandem mass spectrometry. RESULTS: The relative vitamin B-6 vitamer composition of plasma [pyridoxal phosphate (PLP) > pyridoxic acid (PA) > pyridoxal] differed from that of CSF (pyridoxal > PLP > PA > pyridoxamine). Sex influenced vitamin B-6 vitamer concentrations in plasma and CSF and should therefore be taken into account when interpreting vitamin B-6 vitamer concentrations. The strict ratios and strong correlations between vitamin B-6 vitamers point to a tight regulation of vitamin B-6 vitamer concentrations in blood and CSF. Given the unique design of this study, with simultaneously withdrawn blood and CSF from a large number of subjects, reliable CSF:plasma ratios and correlations of vitamin B-6 vitamers could be established. CONCLUSIONS: We provide an extensive reference set of vitamin B-6 vitamer concentrations in plasma and CSF. In addition to providing insight on the regulation of individual vitamers and their intercompartmental distribution, we anticipate that these data will prove to be a valuable reference set for the diagnosis and treatment of conditions associated with altered vitamin B-6 metabolism

D-Amino Acid Aberrations in Cerebrospinal Fluid and Plasma of Smokers

<p>The glutamatergic neurotransmission system and the N-methyl-D-aspartate receptor (NMDAR) have been implicated in smoking and alcohol consumption behavior. Preclinical studies have demonstrated that nicotine and ethanol influence NMDAR functionality, which may have a role in tendencies to consume these substances. Nonetheless, little is known about concentrations of NMDAR coagonists in the cerebrospinal fluid (CSF) and plasma of individuals who smoke or consume alcohol. Glycine and L- and D-stereoisomers of alanine, serine, and proline were therefore measured using ultra-high-performance liquid chromatography-tandem mass spectrometry in 403 healthy subjects. Nicotine and alcohol consumption were quantified using questionnaires. Possible differences in NMDAR coagonist concentrations in plasma and CSF were investigated using ANCOVA with age, body mass index, and storage duration as covariates. The significance threshold was Bonferroni corrected (alpha = 0.00625). Compared with non-smokers, smokers displayed lower levels of D-proline in plasma (p = 0.0027, Cohen's d = -0.41) and D-proline in CSF (p = 0.0026, Cohen's d = -0.43). D-Serine in CSF was higher in smokers than in non-smokers (p = 0.0052, Cohen's d = 0.41). After subdividing participants based on smoking quantity, dose-dependent decreases were demonstrated in smokers for D-proline in plasma (F = 5.65, p = 0.0039) and D-proline in CSF (F = 5.20, p = 0.0060). No differences in NMDAR coagonist levels between alcohol consumption groups were detected. To our knowledge, this is the first report to implicate D-amino acids in smoking behavior of humans. Whether such concentration differences lie at the root of or result from smoking habits may be addressed in prospective studies.</p>