Transfer across the human blood-brain barrier: Evidence for capillary recruitment and for a paradox glucose permeability increase in hypocapnia

The present study was undertaken to investigate whether there is intermittency of capillary flow in the human brain, i.e., whether more capillaries open up at high blood flow thus increasing the surface for diffusional exchange. Unidirectional transfer across the blood-brain barrier of labeled D-glucose, l-phenylalanine, l-leucine, thiourea, and propranolol was measured using the indicator diffusion method with labeled Na⁺, Cl^?, and chelated In as impermeable reference substances. Forty-three patients needing carotid angiography were studied in different situations, rest, hyperventilation, hypercapnia, hypo/hypertension (within the limits of autoregulation). Some older data on the seizure situation are included. Cerebral blood flow (CBF) was measured concomitantly. In situations with high blood flow, extraction (E) decreased and the permeability surface area product (PS) increased for both the lipophilic substances and for those transferred by carrier mechanism. With low CBF the reverse happened except for an unexpected PS increase for glucose in hyperventilation. Variations of PS in parallel with CBF are evidence of capillary recruitment which constitutes a more efficient way of increasing tissue supply. PS and E remained constant with a constant CBF even when arterial blood pressure was changed, indicating that autoregulatory mechanisms do not affect the diffusional exchange surface and probably take place at the arteriolar level. PS for glucose increased in hyperventilation perhaps as an expression of a pH dependence of its carrier.     

Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases

Purpose

Interleukin-6 (IL-6) production and signalling are increased in the inflamed mucosa in inflammatory bowel diseases (IBD). As published serum levels of IL-6 and its soluble receptors sIL-6R and sgp130 in IBD are from small cohorts and partly contradictory, we systematically evaluated IL-6, sIL-6R and sgp130 levels as markers of disease activity in Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

Consecutive adult outpatients with confirmed CD or UC were included, and their disease activity and medication were monitored. Serum from 212 CD patients (815 measurements) and 166 UC patients (514 measurements) was analysed, and 100 age-matched healthy blood donors were used as controls.

Results

IL-6 serum levels were significantly elevated in active versus inactive CD and UC, also compared with healthy controls. However, only a fraction of IBD patients showed increased serum IL-6. IL-6 levels ranged up to 32.7 ng/mL in active CD (>?5000-fold higher than in controls), but also up to 6.9 ng/mL in inactive CD. Increases in active UC (up to 195 pg/mL) and inactive UC (up to 27 pg/mL) were less pronounced. Associations between IL-6 serum levels and C-reactive protein concentrations as well as leukocyte and thrombocyte counts were observed. Median sIL-6R and sgp130 levels were only increased by up to 15%, which was considered of no diagnostic significance.

Conclusions

Only a minority of IBD patients shows elevated IL-6 serum levels. However, in these patients, IL-6 is strongly associated with disease activity. Its soluble receptors sIL-6R and sgp130 do not appear useful as biomarkers in IBD.

     

Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma

OBJECTIVE: To study the expression of Toll-like receptor 2 (TLR-2) and TLR-4 and its association with proinflammatory cytokines in synovial tissue from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and healthy individuals. METHODS: Synovial tissue specimens from 29 RA patients were stained for TLR-2, TLR-4, and proinflammatory cytokines (interleukin-1beta [IL-1beta], IL-12, IL-17, IL-18, and tumor necrosis factor alpha [TNFalpha]). The expression of TLR-2, TLR-4, and cytokines as well as the degree of inflammation in synovial tissue were compared between patients with RA, patients with OA (n = 5), and healthy individuals (n = 3). Peripheral blood mononuclear cells (PBMCs) were incubated with IL-12 and IL-18, and TLR expression was assessed using fluorescence-activated cell sorter analysis. Production of TNFalpha and IL-6 was measured using Luminex bead array technology. RESULTS: In RA synovial tissue, the expression of TLR-2 was slightly higher than that of TLR-4. Interestingly, both TLR-2 and TLR-4 were expressed at higher levels in moderately inflamed synovium, as compared with synovial tissue with no or severe inflammation. TLR expression in both the lining and the sublining was associated with the presence of IL-12 and IL-18, but no other cytokines, in the lining. The expression of both TLRs was low in synovial tissue from OA patients and healthy donors. Stimulation of PBMCs with IL-12 and IL-18 resulted in increased expression of both TLR-2 and TLR-4; this could be blocked with anti-interferon-gamma (anti-IFNgamma) antibodies, suggesting a role for IFNgamma. Lipopolysaccharide- or lipoteichoic acid-mediated triggering of PBMCs incubated with IL-12/IL-18 or IFNgamma led to an increased production of both TNFalpha and IL-6, indicating the functionality of TLR-2 and TLR-4. CONCLUSION: TLR-2 and TLR-4 are expressed in synovial tissue of patients with clinically active disease and are associated with the levels of both IL-12 and IL-18. The synergistic effect of IL-12 and IL-18 on T cell IFNgamma production seems to regulate expression of TLR-2 and TLR-4 in the synovial tissue of RA patients.     

Use of complementary therapies, adherence, and quality of life in lung transplant recipients.

PURPOSES: The purpose of this study was to describe complementary and alternative medicine (CAM) use by lung transplant patients and to determine whether CAM users differ from nonusers with respect to health status, quality of life, or medical adherence. METHODS: A mailed survey seeking CAM, quality of life, and adherence information was sent to 145 lung transplant recipients, and 99 responded. RESULTS: The majority (88%) used at least 1 form of CAM (median, 2; range, 0-17). Prayer (68%), support groups (43%), and relaxation techniques (31%) were the most common. Only 44% of users reported discussing CAM with their providers. CAM users were adherent to their transplant regimen. Few differences were found between CAM users and nonusers. Education, high symptom burden, female sex, and depression symptoms were associated with various types of CAM use. CONCLUSION: Most lung transplant recipients are using CAM. Providers must explore potential for interaction or enhancement between CAM and standard therapy to optimize care.     

Associations of Mortality with Long-Term Exposures to Fine and Ultrafine Particles,Species and Sources: Results from the California Teachers Study Cohort

Background

Although several cohort studies report associations between chronic exposure to fine particles (PM_2.5) and mortality, few have studied the effects of chronic exposure to ultrafine (UF) particles. In addition, few studies have estimated the effects of the constituents of either PM_2.5 or UF particles.

Methods

We used a statewide cohort of > 100,000 women from the California Teachers Study who were followed from 2001 through 2007. Exposure data at the residential level were provided by a chemical transport model that computed pollutant concentrations from > 900 sources in California. Besides particle mass, monthly concentrations of 11 species and 8 sources or primary particles were generated at 4-km grids. We used a Cox proportional hazards model to estimate the association between the pollutants and all-cause, cardiovascular, ischemic heart disease (IHD), and respiratory mortality.

Results

We observed statistically significant (p < 0.05) associations of IHD with PM_2.5 mass, nitrate, elemental carbon (EC), copper (Cu), and secondary organics and the sources gas- and diesel-fueled vehicles, meat cooking, and high-sulfur fuel combustion. The hazard ratio estimate of 1.19 (95% CI: 1.08, 1.31) for IHD in association with a 10-μg/m³ increase in PM_2.5 is consistent with findings from the American Cancer Society cohort. We also observed significant positive associations between IHD and several UF components including EC, Cu, metals, and mobile sources.

Conclusions

Using an emissions-based model with a 4-km spatial scale, we observed significant positive associations between IHD mortality and both fine and ultrafine particle species and sources. Our results suggest that the exposure model effectively measured local exposures and facilitated the examination of the relative toxicity of particle species.

Citation

Ostro B, Hu J, Goldberg D, Reynolds P, Hertz A, Bernstein L, Kleeman MJ. 2015. Associations of mortality with long-term exposures to fine and ultrafine particles, species and sources: results from the California Teachers Study cohort. Environ Health Perspect 123:549–556; http://dx.doi.org/10.1289/ehp.1408565     

Determination of the renal concentration capacity following intravenous administration of dDAVP in healthy humans

The synthetic AVP analogue 1-desamino-8-d-arginine-vasopressin (dDAVP) is used for treatment of polyuric disorders. Lack of commercially available assays limits the usefulness of dDAVP as a diagnostic tool in the assessment of renal concentrating capacity. We aimed to develop a specific radioimmunoassay (RIA) for determination of plasma dDAVP (pdDAVP) in order to investigate the relationship between pdDAVP levels and urine osmolality (Uosm). Further, we aimed to determine the onset, duration, and maximum concentrating capacity following intravenous (i.v.) bolus dDAVP injection. The dDAVP assay was based on a well-established RIA for measurements of AVP. Fourteen healthy subjects (aged 15–18 years) participated. Blood and urine samples were collected prior to and after i.v. bolus of 0.03?µg/kg dDAVP. Diuresis and Uosm was measured for nine hours following dDAVP administration. PdDAVP and Uosm were analyzed.We established a specific RIA for the measurement of pdDAVP. All subjects reached maximal pdDAVP concentration (C_max) 30 minutes following infusion, and a rise in Uosm after 60 minutes. Maximal Uosm varied between subjects, with no direct correlation to the achieved pdDAVP levels. We found no significant intra-individual variation between two dDAVP infusions and the effect was reproducible in terms of C_max and maximal Uosm. We characterized the relationship between pdDAVP and Uosm after dDAVP bolus injection in healthy adolescents using our dDAVP assay. Maximal Uosm achieved correlated with the baseline Uosm levels and seemed unrelated to achieved pdDAVP levels. The urine concentrating response was maintained at least eight hours.     

Patient cohorting and infection control

Patients with cystic fibrosis (CF) have an abnormal propensity for recurrent and chronic infections of the lower respiratory tract (LRT), and the most common cause of a shortened lifespan is chronic infection with Pseudomonas aeruginosa. A few other gram-negative organisms, primarily Burkholderia cepacia complex have, however, emerged as serious pathogens capable of establishing chronic LRT infection. Details of these and other CF pathogens can be found in the article by Dr. John LiPuma, Burkholderia and Emerging Pathogens in Cystic Fibrosis, in this issue. Chronically infected patients constitute a major microbial reservoir from which noninfected patients can be infected with both P. aeruginosa and B. cepacia complex by direct patient-to-patient transmission, and possibly also by exposure to contaminated environments. Other more rare pathogens such as Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and nontuberculous mycobacteria (NTM) appear less capable of causing patient-to-patient transmission. Both the physical proximity and the duration of exposure of noninfected patients to patients chronically infected with P. aeruginosa and B. cepacia complex are important determinants of the risk of cross-infection. Cohorting of patients according to presence or absence of specific pathogens coupled with conventional hygienic precautions can, however, lead to a decrease in incidence and prevalence of chronic infections with these two species, wherefore patient cohorting is now an integral component of infection control in patients with CF.