Release of angiotensin converting enzyme by the lung after Pseudomonas bacteremia in sheep.

We studied release of angiotensin-converting enzyme (ACE) by the lung after acute injury associated with an increase in pulmonary vascular permeability. In eight adult sheep with chronic lung lymph fistulas, we measured lymph flow (QL), and both ACE activity and total protein content in lymph and plasma under base-line conditions and during 24 h after an infusion of live pseudomonas organism. Under base-line conditions, ACE activity in plasma was 4.93 +/- 0.43 U/ml (mean +/- SEM). The [lymph]/[plasma] ([L]/[P]) ratio for ACE was 0.93 +/- 0.18, compared with a ratio of 0.79 +/- 0.08 for albumin (mean +/- SD). We estimated the molecular weight of ovine ACE to be 145,000 by gel chromatography. Predicted [L]/[P] ratio for a molecule this size is 0.51. Thus, a substantial fraction of ACE activity detected lung lymph under base-line conditions (11.1 +/- 6.2 U/h; mean +/- SD) originated in the lung, and did not diffuse passively from plasma. After pseudomonas infusion, endothelial injury was demonstrated by a rise in pulmonary vascular clearance for total protein (Crp = QL X [L]/[P]). Crp = 3.1 +/- 0.6 ml/h before pseudomonas bacteremia, and rose to 6.7 +/- 1.2 ml/h by 2 h after onset of the infusion (means +/- SEM, p less than 0.05). Crp remained significantly elevated for at least 10 h after the infusion. Release of ACE into lung lymph doubled after acute lung injury and equaled 22.3 +/- 13.8 U/h at 4 h after onset of the infusion. ACE secretion into lung lymph had returned to baseline levels by 24 h after bacteremia. We did not observe a significant rise in plasma ACE activity after acute lung injury. Pseudomonas bacteremia in sheep results in acute, reversible lung injury associated with increased pulmonary vascular permeability, and increased release of ACE by the lung. Failure to detect a rise in plasma ACE content might result from dilution in the large vascular pool or rapid catabolism of the enzyme at some site distant from the lung

Functional Characterization of a Trypanosoma brucei TATA-Binding Protein-Related Factor Points to a Universal Regulator of Transcription in Trypanosomes

Transcriptional mechanisms remain poorly understood in trypanosomatid protozoa. In particular, there is no knowledge about the function of basal transcription factors, and there is an apparent rarity of promoters for protein-coding genes transcribed by RNA polymerase (Pol) II. Here we describe a Trypanosoma brucei factor related to the TATA-binding protein (TBP). Although this TBP-related factor (TBP-related factor 4 [TRF4]) has about 31% identity to the TBP core domain, several key residues involved in TATA box binding are not conserved. Depletion of the T. brucei TRF4 (TbTRF4) by RNA interference revealed an essential role in RNA Pol I, II, and III transcription. Using chromatin immunoprecipitation, we further showed that TRF4 is recruited to the Pol I-transcribed procyclic acidic repetitive genes, Pol II-transcribed spliced leader RNA genes, and Pol III-transcribed U-snRNA and 7SL RNA genes, thus supporting a role for TbTRF4 in transcription performed by all three nuclear RNA polymerases. Finally, a search for TRF4 binding sites in the T. brucei genome led to the identification of such sites in the 3′ portion of certain protein-coding genes, indicating a unique aspect of Pol II transcription in these organisms

Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone.

Acute bacterial meningitis may be associated with increased intracranial pressure, neurological sequelae such as communicating hydrocephalus, and a slow response to antibiotic therapy. Alterations in cerebrospinal hydrodynamics are at least partially responsible for these complications. Constant, low-flow short-duration manometric infusion studies through a hollow-bore pressure monitoring device in direct continuity with the supracortical subarachnoid space were performed in rabbits with experimental meningitis. Maximal resistance to cerebrospinal fluid (CSF) outflow from the subarachnoid to vascular space was markedly increaed in acute pneumococcal meningitis when compared to control, uninfected animals (6.77 +/- 3.52 vs. 0.26 +/- 0.04 mm Hg/microliter per min, P less than 0.001). Similar elevations (8.93 +/- 4.15 mm Hg/microliter per min were found in experimental Escherichia coli meningitis. Despite eradication of viable bacteria from the CSF by penicillin therapy during the acute stage of pneumococcal meningitis, resistance remained elevated (6.07 +/- 4.68 mm Hg/microliter per min) and had not returned to normal up to 15 d later. Administration of methylprednisolone during the early stages of acute pneumococcal meningitis reduced mean peak outflow resistance towards control values (0.59 mm Hg/microliter per min) and no "rebound" effect was apparent 24 h later. These hydrodynamic alterations in experimental meningitis prevent normal CSF absorption and decrease the ability of the bran to compensate for changes in intracranial volume and pressure

Data from: Large scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine

Objective: To identify a plasma metabolomic biomarker signature for migraine. Methods: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. Results: Decreases in the level of apolipoprotein A1 (β −0.10; 95% confidence interval [CI] −0.16, −0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β −0.10; 95% CI −0.15, −0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β −0.24; 95% CI −0.36, −0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. Conclusions: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs