Automated tracheal intubation in an airway manikin using a robotic endoscope: a proof of concept study.

Robotic endoscope-automated via laryngeal imaging for tracheal intubation (REALITI) has been developed to enable automated tracheal intubation. This proof-of-concept study using a convenience sample of participants, comprised of trained anaesthetists and lay participants with no medical training, assessed the performance of a robotic device for the insertion of a tracheal tube into a manikin. A prototype robotic endoscope device was inserted into the trachea of an airway manikin by seven anaesthetists and seven participants with no medical training. Each individual performed six device insertions into the trachea in manual mode and six in automated mode. The anaesthetists succeeded with 40/42 (95%) manual insertions (median (IQR [range]) 17 (12-26 [4-132]) s) and 40/42 (95%) automated insertions (15 (13-18 [7-25]) s). The non-trained participants succeeded in 41/42 (98%) manual insertions (median (IQR [range]) 18 (13-21 [8-133]) s) and 42/42 (100%) automated insertions (16 (13-23 [10-58])] s). The duration of insertion did not differ between groups. An effect of increasing experience was observed in both groups in manual mode. A Likert scale for 'ease of use' (0 = very difficult to 10 = very easy) showed similar results within the two groups; the mean (SD) was 5.9 (2.1) for the anaesthetists and 6.9 (1.3) for the non-trained participants. We have successfully performed the first automated tracheal device insertion in a manikin with comparable results in a convenience sample of anaesthetists and lay participants with no medical training.

80% Valley Polarization of Free Carriers in Singly Oriented Single-Layer WS_{2} on Au(111).

We employ time- and angle-resolved photoemission spectroscopy to study the spin- and valley-selective photoexcitation and dynamics of free carriers at the K[over ¯] and K[over ¯]^{'} points in singly oriented single-layer WS_{2}/Au(111). Our results reveal that in the valence band maximum an ultimate valley polarization of free holes of 84% can be achieved upon excitation with circularly polarized light at room temperature. Notably, we observe a significantly smaller valley polarization for the photoexcited free electrons in the conduction band minimum. Clear differences in the carrier dynamics between electrons and holes imply intervalley scattering processes into dark states being responsible for the efficient depolarization of the excited electron population.

Impact of physical exercise on sensor performance of the FreeStyle Libre intermittently viewed continuous glucose monitoring system in people with Type 1 diabetes: a randomized crossover trial.

AIMS: To evaluate the sensor performance of the FreeStyle Libre intermittently viewed continuous glucose monitoring system using reference blood glucose levels during moderate-intensity exercise while on either full or reduced basal insulin dose in people with Type 1 diabetes. METHODS: Ten participants with Type 1 diabetes [four women, mean ± sd age 31.4 ± 9.0 years, BMI 25.5±3.8 kg/m2 , HbA1c 55±7 mmol/mol (7.2±0.6%)] exercised on a cycle ergometer for 55 min at a moderate intensity for 5 consecutive days at the clinical research facility, while receiving either their usual or a 75% basal insulin dose. After a 4-week washout period, participants performed the second exercise period having switched to the alternative basal insulin dose. During exercise, reference capillary blood glucose values were analysed using the fully enzymatic-amperometric method and compared with the interstitial glucose values obtained. Intermittently viewed continuous glucose monitoring accuracy was analysed according to median (interquartile range) absolute relative difference, and Clarke error grid and Bland-Altman analysis for overall glucose levels during exercise, stratified by glycaemic range and basal insulin dosing scheme (P<0.05). RESULTS: A total of 845 glucose values were available during exercise to evaluate intermittently viewed continuous glucose monitoring sensor performance. The median (interquartile range) absolute relative difference between the reference values and those obtained by the sensor across the glycaemic range overall was 22 (13.9-29.7)%, and was 36.3 (24.2-45.2)% during hypoglycaemia, 22.8 (14.6-30.6)% during euglycaemia and 15.4 (9-21)% during hyperglycaemia. Usual basal insulin dose was associated with a worse sensor performance during exercise compared with the reduced (75%) basal insulin dose [median (interquartile range) absolute relative difference: 23.7 (17.2-30.7)% vs 20.5 (12-28.1)%; P<0.001). CONCLUSIONS: The intermittently viewed continuous glucose monitoring sensor showed diminished accuracy during exercise. Absolute glucose readings derived from the sensor should be used cautiously and need confirmation by additional finger-prick blood glucose measurements.

Acute Exercise-Induced Circulating Haematopoietic Stem and Progenitor Cells in Cardiac Patients - A Case Series.

BACKGROUND: Exercise-induced circulating haematopoietic stem and progenitor cell (HPC) number has been discussed in the context of regeneration in heart disease patients. OBJECTIVE: The aim of this pilot study was to compare the effect of different exercise protocols usually applied in cardiac rehabilitation on the number of acute, exercise-induced HPCs, related to potential mediators, e.g. biomarkers of sympathetic and oxidative stress, and inflammation. METHODS: This is a case series comprising seven patients suffering from coronary heart disease (CHD) undertaken at the Center for Ambulant Cardiac Rehabilitation. Patients (n=6) performed two exercise modes (constant-load, CLE; high-intensity interval, HIIE) in randomised order. Venous blood was drawn before and immediately after each test to assess CD34+/CD45+ HPC number by flow cytometry and biomarkers in blood plasma. The primary outcome was the change in HPC number, the secondary outcomes were changes in sympathetic/oxidative stress and markers of inflammation. RESULTS: Both exercise modes resulted in a non-significant increase in HPC number after exercise, even when the results of both tests were combined. Overall, free norepinephrine increased significantly and was positively related to exercise-induced HPC number (r=0.70, p<0.05). Markers of sympathetic activation (fNE), oxidative stress (myeloperoxidase) and inflammation (interleukin-6) significantly increased after CLE and HIIE with no difference between tests. CONCLUSIONS: Interestingly, acute CLE and HIIE did not stimulate significant HPC mobilisation in CHD, although both exercise modes elevated circulating concentrations of sympathetic activation. Haematopoietic stem and progenitor cell mobilisation could be blunted due to disease-related bone-marrow exhaustion.

[Mortality after high-risk surgery in Jehovah's Witness patients]. / Letalität nach operativen Risikoeingriffen bei Zeugen Jehovas.

BACKGROUND: Jehovah's Witness (JW) patients strictly refuse allogeneic blood transfusion for religious reasons. Nevertheless, JW also wish to benefit from modern therapeutic concepts including major surgical procedures without facing an excessive risk of death. The Northwest Hospital in Frankfurt am Main Germany is a confidential clinic of JW and performs approximately 100 surgical interventions per year on this patient group. MATERIAL AND METHODS: A retrospective analysis of closed medical cases performed in the years 2008-2018 at the Northwest Hospital aimed to clarify (1) the frequency of surgical procedures in JW patients associated with a statistical allogeneic transfusion risk (presence of preoperative anemia and/or in-house transfusion probability >10%) during this time period, (2) the degree of acceptance of strategies avoiding blood transfusion by JW and (3) the anemia-related postoperative mortality rate in JW patients. RESULTS: In the 11- year observation period 123 surgical procedures with a relevant allogeneic transfusion risk were performed in 105 JW patients. Anemia according to World Health Organization (WHO) criteria was present in 44% of cases on the day of surgery. Synthetic and recombinant drugs (tranexamic acid, desmopressin, erythropoetin, rFVIIa) were generally accepted, acute normovolemic hemodilution (ANH) in 92% and cell salvage in 96%. Coagulation factor concentrates extracted from human plasma and therefore generally refused by JW so far, were accepted by 83% of patients following detailed elucidation. Out of 105 JW patients 7 (6.6%) died during the postoperative hospital stay. In 4 of the 7 fatal cases the cause of death could be traced back to severe postoperative anemia. CONCLUSION: Given optimal management JW patients can undergo major surgery without an excessive risk of death. The 6.6% in-hospital mortality observed in this institution was in the range of the 4% generally observed after surgery in Europe. The majority of JW patients accepted a variety of blood conservation strategies following appropriate elucidation. This also included coagulation factor concentrates extracted from human plasma enabling an effective treatment of even severe bleeding complications. In this analysis postoperative hemoglobin concentrations below 6 g/dl in older JW patients were associated with a high mortality risk due to anemia.

Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function.

Although amateur sports have become increasingly competitive within recent decades, there are as yet few studies on the possible health risks for athletes. This study aims to determine the impact of ultra-endurance exercise-induced stress on the number and function of circulating hematopoietic progenitor cells (CPCs) and hematological, inflammatory, clinical, metabolic, and stress parameters in moderately trained amateur athletes. Following ultra-endurance exercise, there were significant increases in leukocytes, platelets, interleukin-6, fibrinogen, tissue enzymes, blood lactate, serum cortisol, and matrix metalloproteinase-9. Ultra-endurance exercise did not influence the number of CPCs but resulted in a highly significant decline of CPC functionality after the competition. Furthermore, Epstein-Barr virus was seen to be reactivated in one of seven athletes. The link between exercise-induced stress and decline of CPC functionality is supported by a negative correlation between cortisol and CPC function. We conclude that ultra-endurance exercise induces metabolic stress and an inflammatory response that affects not only mature hematopoietic cells but also the function of the immature hematopoietic stem and progenitor cell fraction, which make up the immune system and provide for regeneration.

Excitation of coherent phonons in the one-dimensional Bi(114) surface.

We present time-resolved photoemission experiments from a peculiar bismuth surface, Bi(114). The strong one-dimensional character of this surface is reflected in the Fermi surface, which consists of spin-polarized straight lines. Our results show that the depletion of the surface state and the population of the bulk conduction band after the initial optical excitation persist for very long times. The disequilibrium within the hot electron gas along with strong electron-phonon coupling cause a displacive excitation of coherent phonons, which in turn are reflected in coherent modulations of the electronic states. Beside the well-known A(1g) bulk phonon mode at 2.76 THz, the time-resolved photoelectron spectra reveal a second mode at 0.72 THz which can be attributed to an optical surface phonon mode along the atomic rows of the Bi(114) surface.

Injurious pecking in organic turkey fattening-effects of husbandry and feeding on injuries and plumage damage of a slow- (Auburn) and a fast-growing (B.U.T.6) genotype.

Injuries and plumage damage (PD) are important indicators of welfare. First priority in turkey fattening is to reduce injurious pecking, which includes aggressive pecking (agonistic behavior) and additionally severe feather pecking (SFP) and cannibalism with their multifactorial reasons. Still, there are few studies available evaluating different genotypes for their welfare status under organic conditions. The aim of this study was to investigate the effects of genotype and husbandry with 100% organic feeding (2 variants with different riboflavin content: V1 and V2) on injuries and PD. During rearing nonbeaktrimmed male turkeys of a slow- (Auburn, n = 256) and fast-growing (B.U.T.6, n = 128) genotype were kept in 2 indoor housing systems (without environmental enrichment (EE) = H1-, n = 144 and with EE = H2+, n = 240). During fattening 13 animals per pen of H2+ were relocated to a free-range system (H3 MS, n = 104). EE included pecking stones, elevated seating platforms and silage feeding. The study included five 4-wk feeding phases. At the end of each phase, injuries and PD were scored to assess animal welfare. Injury scores ranged from 0 (=no damage) to 3 (=severe damage) and PD from 0 to 4. Injurious pecking was observed from the 8th week onward (injuries: 16.5% and PD: 31.4%). Binary logistic regression models showed that both indicators were affected by genotype (each P < 0.001), husbandry (each P < 0.001), feeding (injuries P = 0.004; PD P = 0.003), and age (each P < 0.001). Auburn showed less injuries and PD than B.U.T.6. H1- had the fewest injuries and PD for Auburn animals compared to H2+ or H3 MS. In summary, the use of alternative genotypes (Auburn) in organic fattening improved welfare, but keeping them in free-range systems or in husbandry with EE, does not lead to a reduction of injurious pecking. Therefore, further studies are needed with more and changing enrichment materials, further management measures, changes in housing structure, and even more intensive animal care.

Sex-specific effects of spironolactone on blood pressure in gonadectomized male and female Wistar rats.

A low-salt diet is known to decrease and salt excess to increase blood pressure in humans and rodents. Sex steroids seem to play a role in salt dependent hypertension. However, little is known about sex differences in mineralocorticoid receptor blockade between male and female rats. The objective of the work was at first to investigate the effects of a low-salt vs. a high-salt diet on blood pressure without the influence of gonadal steroids in male and female rats. Second, to determine the sex-specific effects of mineralocorticoid receptor blockade by spironolactone in high-salt and low-salt fed gonadectomized male and female animals. Normotensive male and female Wistar rats were gonadectomized and put on a low (NaCl<0.03%) or high (NaCl=4%) salt diet. On each diet animals received spironolactone or placebo. Blood pressure was measured by tail-cuff-method; 24-h urine samples were collected in metabolic cages and blood was collected for hormonal measurements. High-salt diet significantly increased systolic blood pressure in both sexes. This effect could be blocked effectively by spironolactone only in male rats. Spironolactone treatment significantly increased aldosterone levels in males and females independent of the sodium content of the diet. High sodium diet significantly increased relative kidney weight, which was not altered by spironolactone treatment. Independently of gonadal steroids a high-salt diet increased blood pressure in gonadectomized male and female rats. Spironolactone lowered blood pressure only in male not in female rats on a high-salt diet clearly indicating sex-specific effects of the mineralo-corticoid antagonist spironolactone.

Agreement between heart rate deflection point and maximal lactate steady state in young adults with different body masses.

We examined the agreement between heart rate deflection point (HRDP) variables with maximal lactate steady state (MLSS) in a sample of young males categorized to different body mass statuses using body mass index (BMI) cut-off points. One hundred and eighteen young males (19.9 ± 4.4 years) underwent a standard running incremental protocol with individualized speed increment between 0.3 and 1.0 km/h for HRDP determination. HRDP was determined using the modified Dmax method called S.Dmax. MLSS was determined using 2-5 series of constant-speed treadmill runs. Heart rate (HR) and blood lactate concentration (La) were measured in all tests. MLSS was defined as the maximal running speed yielding a La increase of less than 1 mmol/L during the last 20 min. Good agreement was observed between HRDP and MLSS for HR for all participants (±1.96; 95% CI = -11.5 to +9.2 b/min, ICC = 0.88; P < 0.001). Good agreement was observed between HRDP and MLSS for speed for all participants (±1.96; 95% CI = -0.40 to +0.42 km/h, ICC = 0.98; P < 0.001). The same findings were observed when participants were categorized in different body mass groups. In conclusion, HRDP can be used as a simple, non-invasive and time-efficient method to objectively determine submaximal aerobic performance in nonathletic young adult men with varying body mass status, according to the chosen standards for HRDP determination.

The occupied electronic structure of ultrathin boron doped diamond.

Using angle-resolved photoelectron spectroscopy, we compare the electronic band structure of an ultrathin (1.8 nm) δ-layer of boron-doped diamond with a bulk-like boron doped diamond film (3 µm). Surprisingly, the measurements indicate that except for a small change in the effective mass, there is no significant difference between the electronic structure of these samples, irrespective of their physical dimensionality, except for a small modification of the effective mass. While this suggests that, at the current time, it is not possible to fabricate boron-doped diamond structures with quantum properties, it also means that nanoscale boron doped diamond structures can be fabricated which retain the classical electronic properties of bulk-doped diamond, without a need to consider the influence of quantum confinement.

Changes in brain metabolism after ECT-positron emission tomography in the assessment of changes in glucose metabolism subsequent to electroconvulsive therapy--lessons, limitations and future applications.

BACKGROUND: Electroconvulsive therapy (ECT) has been used as an effective treatment option in severe and treatment resistant cases of depression for decades. However the mode of action of ECT is still not fully understood. Advances in neuroimaging created new possibilities to understand the functional changes of the human brain. METHODS: Literature review of studies assessing possible changes in cerebral glucose metabolism pre- and post-ECT by PET, identified by PubMed. RESULTS: Studies were limited by small sample size, inhomogeneous study population with uni- and bipolar depressive patients and methodological inconsistencies. Despite considerable variance, reduction in glucose metabolism after ECT in bilateral anterior and posterior frontal areas represented the most consistent findings. CONCLUSIONS: Future research into this issue should include larger and more consistent cohorts of patients. Assessing clinical improvement of depression after ECT should allow to correlate changes in brain glucose metabolism with functional scores. Follow up PET scans after six or twelve months should be performed to test if changes in brain metabolism are persistent.

Oral magnesium therapy, exercise heart rate, exercise tolerance, and myocardial function in coronary artery disease patients.

BACKGROUND: Previous studies have demonstrated that in patients with coronary artery disease (CAD) upward deflection of the heart rate (HR) performance curve can be observed and that this upward deflection and the degree of the deflection are correlated with a diminished stress dependent left ventricular function. Magnesium supplementation improves endothelial function, exercise tolerance, and exercise induced chest pain in patients with CAD. PURPOSE: We studied the effects of oral magnesium therapy on exercise dependent HR as related to exercise tolerance and resting myocardial function in patients with CAD. METHODS: In a double blind controlled trial, 53 male patients with stable CAD were randomised to either oral magnesium 15 mmol twice daily (n = 28, age 61+/-9 years, height 171+/-7 cm, body weight 79+/-10 kg, previous myocardial infarction, n = 7) or placebo (n = 25, age 58+/-10 years, height 172+/-6 cm, body weight 79+/-10 kg, previous myocardial infarction, n = 6) for 6 months. Maximal oxygen uptake (VO2max), the degree and direction of the deflection of the HR performance curve described as factor k<0 (upward deflection), and the left ventricular ejection fraction (LVEF) were the outcomes measured. RESULTS: Magnesium therapy for 6 months significantly increased intracellular magnesium levels (32.7+/-2.5 v 35.6+/-2.1 mEq/l, p<0.001) compared to placebo (33.1+/-3.1.9 v 33.8+/-2.0 mEq/l, NS), VO2max (28.3+/-6.2 v 30.6+/-7.1 ml/kg/min, p<0.001; 29.3+/-5.4 v 29.6+/-5.2 ml/kg/min, NS), factor k (-0.298+/-0.242 v -0.208+/-0.260, p<0.05; -0.269+/-0.336 v -0.272+/-0.335, NS), and LVEF (58+/-11 v 67+/-10%, p<0.001; 55+/-11 v 54+/-12%, NS). CONCLUSION: The present study supports the intake of oral magnesium and its favourable effects on exercise tolerance and left ventricular function during rest and exercise in stable CAD patients.

Novel shielding materials for space and air travel.

The reduction of dose onboard spacecraft and aircraft by appropriate shielding measures plays an essential role in the future development of space exploration and air travel. The design of novel shielding strategies and materials may involve hydrogenous composites, as it is well known that liquid hydrogen is most effective in attenuating charged particle radiation. As precursor for a later flight experiment, the shielding properties of newly developed hydrogen-rich polymers and rare earth-doped high-density rubber were tested in various ground-based neutron and heavy ion fields and compared with aluminium and polyethylene as reference materials. Absorbed dose, average linear energy transfer and gamma-equivalent neutron absorbed dose were determined by means of LiF:Mg,Ti thermoluminescence dosemeters and CR-39 plastic nuclear track detectors. First results for samples of equal aerial density indicate that selected hydrogen-rich plastics and rare-earth-doped rubber may be more effective in attenuating cosmic rays by up to 10% compared with conventional aluminium shielding. The appropriate adaptation of shielding thicknesses may thus allow reducing the biologically relevant dose. Owing to the lower density of the plastic composites, mass savings shall result in a significant reduction of launch costs. The experiment was flown as part of the European Space Agency's Biopan-5 mission in May 2005.

Effects of partial extraction of light chain 2 on the Ca2+ sensitivities of isometric tension, stiffness, and velocity of shortening in skinned skeletal muscle fibers.

Various functional roles for myosin light chain 2 (LC2) have been suggested on the basis of numerous and predominantly in vitro biochemical studies. Using skinned fibers from rabbit psoas muscle, the present study examines the influence of partial removal of LC2 on isometric tension, stiffness, and maximum velocity of shortening at various levels of activation by Ca2+. Isometric tension, stiffness, and velocity of shortening were measured at pCa values between 6.6 and 4.5 (a) in a control fiber segment, (b) in the same fiber segment after partial removal of LC2, and (c) after recombination with LC2. The extraction solution contained 20 mM EDTA, 20 or 50 mM KCl, and either imidazole or PO4(2-) as a pH buffer (pH 7.0). The amount of LC2 extracted varied with the temperature, duration of extraction, and whether or not troponin C (0.5 mg/ml) was added to the extraction solution. Extraction of 20-40% LC2 resulted in increased active tensions in the range of pCa's between 6.6 and 5.7, but had no effect upon maximum tension. The tension-pCa relationship was left-shifted to lower [Ca2+] by as much as 0.2 pCa units after LC2 extraction. At low concentrations of Ca2+, an increase in stiffness proportional to the increase in tension was observed. Readdition of LC2 to these fiber segments resulted in a return of tension and stiffness to near control values. Stiffness during maximal activation was unaffected by partial extraction of LC2. LC2 extraction was shown to uniformly decrease (by 25-30%), the velocity of shortening during the high velocity phase but it did not significantly affect the low velocity phase of shortening. This effect was reversed by readdition of purified LC2 to the fiber segments. On the basis of these findings we conclude that LC2 may modulate the number of cross-bridges formed during Ca2+ activation and also the rate of cross-bridge detachment during shortening. These results are consistent with the idea that LC2 may modulate contraction via an influence upon the conformation of the S1-S2 hinge region of myosin.

Alterations in Ca2+ sensitive tension due to partial extraction of C-protein from rat skinned cardiac myocytes and rabbit skeletal muscle fibers.

C-protein, a substantial component of muscle thick filaments, has been postulated to have various functions, based mainly on results from biochemical studies. In the present study, effects on Ca(2+)-activated tension due to partial removal of C-protein were investigated in skinned single myocytes from rat ventricle and rabbit psoas muscle. Isometric tension was measured at pCa values of 7.0 to 4.5: (a) in untreated myocytes, (b) in the same myocytes after partial extraction of C-protein, and (c) in some myocytes, after readdition of C-protein. The solution for extracting C-protein contained 10 mM EDTA, 31 mM Na2HPO2, 124 mM NaH2PO4, pH 5.9 (Offer et al., 1973; Hartzell and Glass, 1984). In addition, the extracting solution contained 0.2 mg/ml troponin and, for skeletal muscle, 0.2 mg/ml myosin light chain-2 in order to minimize loss of these proteins during the extraction procedure. Between 60 and 70% of endogenous C-protein was extracted from cardiac myocytes by a 1-h soak in extracting solution at 20-23 degrees C; a similar amount was extracted from psoas fibers during a 3-h soak at 25 degrees C. For both cardiac myocytes and skeletal muscle fibers, partial extraction of C-protein resulted in increased active tension at submaximal concentrations of Ca2+, but had little effect upon maximum tension. C-protein extraction also reduced the slope of the tension-pCa relationships, suggesting that the cooperativity of Ca2+ activation of tension was decreased. Readdition of C-protein to previously extracted myocytes resulted in recovery of both tension and slope to near their control values. The effects on tension did not appear to be due to disruption of cooperative activation of the thin filament, since C-protein extraction from cardiac myocytes that were 40-60% troponin-C (TnC) deficient produced effects similar to those observed in cells that were TnC replete. Measurements of the tension-pCa relationship in skeletal muscle fibers were also made at a sarcomere length of 3.5 microns which, because of the distribution of C-protein on the thick filament, should eliminate any interaction between C-protein and actin. The effects of C-protein extraction were similar at long and short sarcomere lengths. These data are consistent with a model in which C-protein modulates the range of movement of myosin, such that the probability of myosin binding to actin is increased after its extraction.

Susceptibility of mononuclear phagocytes to influenza A virus infection and possible role in the antiviral response.

Among leukocytes, only monocytes and macrophages were found to be highly susceptible to an infection by influenza A virus. After infection, de novo viral protein synthesis was initiated but then interrupted after 4-6 h. Most macrophages died by apoptosis within 25-30 h. Before cell death, however, macrophages responded to influenza A virus with a high cytokine gene transcription and subsequent release of tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, interferon (IFN)-alpha/beta, and CC-chemokines. The basic mechanisms of virus-induced cytokine expression are still unknown and appear to involve transcription factors such as nuclear factor-kappaB and AP-1 which, however, were only activated for 2 h and declined below control values thereafter. After influenza A virus infection, only the mononuclear cell attracting CC-chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES were produced while the prototype neutrophil CXC-chemoattractants IL-8 and GRO-alpha were entirely suppressed. This selective induction of CC-chemokines may explain the preferential influx of mononuclear leukocytes into virus-infected tissue. Our data show that monocytes and macrophages represent a primary target for an influenza A virus infection. Thus, the mononuclear phagocyte response leads to a rapid proinflammatory reaction and an enhanced immigration of mononuclear leukocytes, which may condition the infected host for the subsequent virus antigen-specific defense.

Selective induction of the monocyte-attracting chemokines MCP-1 and IP-10 in vesicular stomatitis virus-infected human monocytes.

It is characteristic of viral infections that monocytes/macrophages and lymphocytes infiltrate infected tissue, and neutrophils are absent. CC and non-ELR CXC chemokines predominantly attract mononuclear leukocytes, whereas the ELR motif-expressing CXC chemokines primarily act on neutrophils. To investigate the general role of chemokines in viral diseases, we determined their release and expression patterns after infection of human monocytes with vesicular stomatitis virus (VSV). Human monocytes were productively infected by VSV. Surprisingly, VSV did not induce the release of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6. In contrast, we found a strong induction of the CC chemokine monocyte chemotactic protein-1 (MCP-1) and the non-ELR CXC chemokine interferon-gamma (IFN-gamma) inducible protein-10 (IP-10) by VSV on the gene and protein level. The expression and release of the neutrophil chemoattractants IL-8 and growth-related oncogene-alpha (GRO-alpha) remained unaffected after VSV infection. Our results indicate that the typical monocyte and lymphocyte-dominated leukocyte infiltration of virus-infected tissue is based on a selective induction of mononuclear leukocyte-attracting chemokines.

Toxicologic and pharmacokinetic analysis of intravitreal injections of foscarnet, either alone or in combination with ganciclovir.

PURPOSE: The retinal toxicity of single and repeated intravitreal injections of foscarnet was investigated. In addition, the effects of a combination of foscarnet and ganciclovir were studied, and a pharmacokinetic study to determine the ocular pharmacokinetics of foscarnet after intravitreal injection was carried out. METHODS: Forty rabbits (both albino and pigmented) were used in this study. The electroretinographic (ERG) a-waves and b-waves and oscillatory potentials (OP) were used as as indicators of retinal toxicity. Potential toxicity was also assessed by ophthalmoscopy and histologic studies (light and electron microscopy). RESULTS: The a-wave and b-wave were not deteriorated with 2.4 mg foscarnet after single or repeated injections. The OP remained unchanged. There was no ERG change after intravitreal injection of a combination of both drugs. No evidence of retinal toxicity was observed by indirect ophthalmoscopy in any case. Light and electron microscopy on semithin sections of retina failed to demonstrate any adverse effects, and showed normal organization and cytoarchitecture of all the layers of the retina without evidence of cytopathology. The ocular pharmacokinetics of foscarnet determined by noncompartmental analysis showed a 34-hour terminal elimination half-life and an apparent volume of distribution of 1.9 ml. CONCLUSIONS: Based on these results, high doses of foscarnet were not judged toxic to the rabbit retina, with single or repeated injections. Moreover, concomitant injection of the two drugs did not induce any retinal toxicity. These findings suggest that when systemic treatment is to be stopped in patients with AIDS for toxic side effects, either ganciclovir or foscarnet may be used intravitreally as an alternative. Because a combination of the two drugs has been shown to be synergistic, both ganciclovir and foscarnet might be simultaneously injected into the vitreous cavity to block progression of cytomegalovirus retinitis.