The role of complement in the induction of antibody responses.

To determine the effect of complement on the normal antibody response to T cell-dependent antigens, we immunized normal and C4 deficient guinea-pigs with bacteriophage phi X 174. Following primary immunization with a standard dose (2 X 10(9) PFU/Kg) given intravenously. C4 deficient guinea-pigs produced less antibody than normal guinea-pigs and were unable to maintain measurable antibody levels. Following secondary immunization, antigen clearance of C4 deficient guinea-pigs was delayed and the subsequent antibody response was identical to their primary response without amplification or isotype switch. Increased antigen dose and administration of antigen in adjuvants into footpads improved the responses but did not make them normal. The primary and secondary responses became essentially normal, however, when small amounts of normal guinea-pig serum were given to the deficient animals at the time of the primary (but not the secondary) immunization. We postulate that the contribution of complement to the mature humoral immune response is related to activation of C3. Our data show that antigen initiates a primary immune response. The resultant antigen-antibody complexes interact with complement and are then non-specifically trapped by C3 receptors on dendritic cells, B cells and macrophages. Thus, antigen is selectively accumulated within the lymphoid organs and in turn 'captures' antigen specific B cells by interaction of the trapped antigen with antigen specific sIg. The approximation of specific lymphoid cells, macrophages and antigen permits generation of specific memory cells and ensures prompt, mature antibody response on subsequent antigen exposure.     

When neuroscience gets wet and hardcore: neurocognitive markers obtained during whole body water immersion

Neutral buoyancy facilities are used to prepare astronauts and cosmonauts for extra vehicular activities e.g. on-board of the International Space Station. While previous studies indicated a decrease in cognitive performance in an under water setting, they have only provided behavioural data. This study aimed to review whether recording of electro cortical activity by the use of electroencephalography (EEG) is possible in an under water setting and if so, to identify the influence of water immersion at a depth of 4 m on neurocognitive markers. Ten male subjects performed a cognitive choice-reaction times (RT) task that progressed through five levels of increasing difficulty on land and when submerged 4 m under water. N200 latency and amplitude in the occipital and frontal areas were measured, and baseline cortical activity was measured during rest in both conditions. Neither RT nor amplitude or latency of the N200 showed any significant changes between the land and the under water conditions. Also theta, alpha and beta frequencies showed no differences between the two conditions. The data provided in this study demonstrate the possibility of recording EEG even under the extreme conditions of full body water immersion. The lack of cognitive impairment in RT and N200 in the under water condition may be explained by the fact that only experienced divers participated in the study. As a proof of principle, this study generates many new experimental possibilities that will improve our understanding of cognitive processes under water.     

Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration.

This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C(u,plasma)) to predict brain unbound concentration (C(u,brain)). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The C(u,brain) was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl-]sarcosine, had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C(CSF) and C(u,plasma) represent C(u,brain) equally well; for efflux substrates or slow brain penetration compounds, C(CSF) appears to be equivalent to or more accurate than C(u,plasma) to represent C(u,brain). Thus, we hypothesize that C(CSF) is equivalent to or better than C(u,plasma) to predict C(u,brain). This hypothesis is supported by the literature data.     

Myoelectric analysis of the paraspinal musculature in relation to automobile driving

In this study, the myoelectric activity of 12 paraspinal muscles of ten men aged 18-24 was recorded to examine the effects of backrest inclination and lumbar support in relation to driving. In total, 24 test conditions were evaluated over a 3.5-hour period in a single day. These tests were then repeated, changing the sequence over the next 4 days. The results indicate a complex interaction between the thoracic and lumbar regions of the back with the lowest myoelectric activity position of 120 degrees backrest inclination, 5 cm of lumbar support, and 13.5-18.5 degrees of seat inclination. Electromyogramatic (EMG) evidence of fatigue was not identified over a 3.5-hour period. The generally low levels of EMG activity and, presumably, disc pressure present in any seating position suggest that the paraspinal muscle activity may not play the predominant role in disc herniation as it relates to automobile driving.     

A quantitative analysis of the interactions of antipneumococcal antibody and complement in experimental pneumococcal bacteremia.

The mechanism of protection of type-specific antipneumococcal antibody and complement in bacteremia was investigated with purified rabbit antibody and a guinea pig model of pneumococcal bacteremia. IgG and IgM were isolated from the sera of rabbits immunized with type 7 pneumococci (Pn), and their binding to Pn was quantitated. The number of antibody-binding sites on the pnuemococcal capsule was also determined. Pn were incubated with various amounts of the immunoglobulin preparations before intravenous injection into nonimmune guinea pigs. Whereas 120 molecules of IgM per Pn were sufficient to enhance bloodstream clearance of Pn, 1,400 molecules of IgG per bacterium were required to produce this effect. As the amount of either IgG or IgM added to the Pn was increased, the rate of bloodstream clearance accelerated. In striking contrast, greater than 1,000 molecules of IgM had no effect on the rate of clearance in C4-deficient guinea pigs, which cannot activate complement via the classic pathway. Similarly, 5,000 molecules of IgG had only minimal effect in C4-deficient guinea pigs, and 24,000 molecules of IgG had no effect in guinea pigs depleted of complement by cobra venom factor. Thus, the in vivo opsonic effects of both IgG and IgM anticapsular antibody are mediated via their ability to activate complement. IgG anti-pneumococcal cell wall antibody, raised by intravenous injection of rabbits with unencapsulated Pn, had no effect on the rate of bloodstream clearance of Pn or on the polymorphonuclear leukocyte killing of type 7 Pn in an in vitro bacterial assay. Because the opsonic effects of anticapsular antibody required complement activation, the ability of anticell wall IgG to activate complement was compared with the two classes of anticapsular antibody. As judged by depletion of C3 and C4 from guinea pig serum, as well as by the fixation of radiolabeled C3 to Pn, IgM anticapsular antibody was the best complement activator. However, anticell wall IgG was somewhat more active than anticapsular IgG in each of these tests of complement activation and fixation. When equivalent amounts of C3 were fixed to Pn by each of the three antibodies, Pn sensitized with IgG and IgM anticapsular antibodies caused immune adherence, whereas Pn sensitized with anticell wall IgG did not. This may explain the failure of anticell wall antibody of mediate complement-dependent phagocytosis of Pn in vivo or in vitro. Although anticell wall IgG is capable of activating complement and fixing C3 to Pn, it is not opsonic; the most likely reason is that the nonopsonic antibody mediates C3 deposition in sites on the Pn that cannot interact efficiently with phagocytic cell C3 receptors.     

Virulent Streptococcus viridans bacterial endocarditis

A particularly virulent form of bacterial endocarditis due to Streptococcus viridans is described in selected patients. The diagnosis of purulent pericarditis and myocardial abscess is delineated. In addition, emphasis is placed on early surgical intervention in the appropriale management of these potentially lethal complications.