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This points to a role for the hippocampus in imagination, in addition to its established role in episodic long-term memory Kinsbourne and Wood, ; O'Keefe and Nadel, ; Squire, ; Eichenbaum and Cohen, Burgess and colleagues have suggested that the same processes used to orient oneself in the real world are recruited when imagining being in an environment Becker and Burgess, ; Burgess et al. Electrophysiological studies of the spatial firing properties of neurons in the hippocampal formation of freely moving rodents have offered considerable insight into these processes.

The importance of environmental boundaries, as opposed to a single landmark, for hippocampally mediated location learning was highlighted by Doeller et al. On the basis of their findings and the place cell literature, Doeller et al. Accordingly, increasing the number of enclosing environmental boundaries should boost the contribution of the hippocampus to orientation within that environment.

A similar prediction can be made for orientation within an imagined environment. We aimed to test this hypothesis in the current experiment. Participants were shown aerial views of simple environments made of walls and towers and then required to imagine standing within the environments. We varied parametrically the number of enclosing walls in the imagined scenes, while keeping the overall number of structural elements constant. As a nonspatial, difficulty control, we also varied the colors of the structural elements.

Sixteen male participants aged All were right-handed with normal or corrected-to-normal vision and reported to be in good health with no history of neurological disease. Data from two of the participants were unusable as a result of technical problems during acquisition. Environments comprised a gray, flat ground and a uniform blue sky and contained environmental features walls and towers built of colored red or green blocks.

All environments contained a total of five environmental features made out of blocks in total. Boundariness had five levels Fig. Color complexity had four levels Fig. Screenshots of the environments used for the encoding phase see below were taken from eight equally separated aerial viewpoints and showed the layout of all walls and towers. Screenshots used for the test phase were taken from the point of view of an observer standing on the ground in the center of the environment facing eight equally separated directions.

A final condition used complex three-dimensional structures comprising blocks of mixed colors presented in front of a uniform gray background supplemental Fig. Screenshots of the structures were taken from eight equally spaced viewpoints facing toward its center of mass. Examples of stimuli used in different conditions.

All environments had five structural elements walls or towers. There were five levels of boundary, from zero to four walls. There were four levels of color, aimed to be of increasing complexity to imagine. No behavioral measures differentiated the levels mixed 1 and mixed 2 so these were combined for the imaging analyses. Subjects were asked to imagine standing on the central yellow dot and visualizing the environments from this location.

First, the task was described in detail and participants were talked through four example trials. At the start of each example trial, the participant was shown an aerial screenshot of the environment Fig. They were told that their task would be to imagine being in such an environment.

The experimenter then opened the environment in the virtual-reality program Unreal, which shows the environment from a moveable first-person perspective. The experimenter also moved the viewpoint to one of the walls and to the bottom of one of the towers and panned the viewpoint upward to illustrate the scale of the walls and towers relative to the observer.

It was stressed that, during the main task, participants should try to imagine the environments from the same perspective as shown in the demonstration, i. Task design. After a variable intertrial interval ITI , subjects were shown an aerial view of the to-be-imagined scene. An auditory tone signaled the end of the visualization period, and subjects were asked to rate the vividness of their imaged scene using the keypad rating question.

After a response or after 3. They had 3. Each trial started with the presentation of a cue image an aerial screenshot for 3. Participants closed their eyes and imagined standing in the middle of the cued environment and visualize as accurately as possible the locations and colors of the environmental features consistent with facing a particular direction as chosen by the participant.

An audio tone signaled the end of the visualization period at which point the participant opened their eyes. The screenshot was either consistent with the imagined environment but note that it would only show a subset of the environmental features from an arbitrary viewpoint or it was inconsistent either the colors of the features were wrong or their spatial configuration was wrong, but never both. The purpose of the test was to ensure that participants visualized the correct layout and colors of the environments and also to reinforce that they should imagine the environments from ground-level rather than from the aerial view shown in the cue phase.

The data from these trials will not be considered further for more details, see supplemental Fig. After scanning, participants were shown examples of all of the environments and structures that had been used in the experiment shown as aerial views and were required to rate each one for how easy it had been to visualize during the task on a point scale 1 for very easy, 10 for very difficult.

The purpose of this rating was to obtain a subjective difficulty rating that was not affected by trial-by-trial fluctuations in attention and when the relative difficulty of each trial could be judged, after having experienced all of the environments. There were 75 trials in total 60 environments and 15 structures. The test image was consistent with the imagined environment on 44 of 60 trials and with the imagined structure on 12 of 15 trials.

Trials were presented in a pseudorandom order in two runs separated by a short break during which the participant remained within the scanner the first run comprised 40 trials, the second comprised 35 trials. Trial order was identical for all participants. The sequence was optimized to minimize signal dropout in the medial temporal lobes Weiskopf et al.

In addition, a field map using a double-echo fast, low-angle shot sequence was recorded for distortion correction of the acquired echo planar images Weiskopf et al. After the functional scans, a T1-weighted structural image 1 mm 3 resolution was acquired for coregistration and display of the functional data.

All preprocessing and statistical analyses were performed using SPM8 www. Each subject's structural scan was coregistered to a mean image of their realigned functional scans and then used to calculate transformation parameters for normalizing the functional images to the Montreal Neurological Institute MNI template brain.

The first five EPI volumes were discarded to allow for T1 equilibration. Echo planar images were spatially realigned to the first image in the times series and were corrected for distortions based on the field map Hutton et al. Finally, the normalized functional images were spatially smoothed with an isotropic 8 mm full-width at half-maximum Gaussian kernel.

Structural scans were normalized and averaged using the DARTEL toolbox Ashburner, , and these mean images were used to display the data. After preprocessing, statistical analysis was performed using a general linear model.

For most of the analyses, our interest was in the 10 s imagination phase, which was modeled as a boxcar function 10 s duration and convolved with the canonical hemodynamic response function HRF to create regressors of interest. In several analyses, the imagination phase was parametrically modulated by a variable see below to create the regressors of interest. The cue phase and question phase were also modeled as boxcar functions 3. Trials in which an incorrect response had been made using the highest confidence category were modeled separately and included as regressors of no interest.

For each participant, each session was modeled separately. The parameter estimates were entered into a second-level random-effects analysis. That is, for each voxel in the brain, single-sample t tests were used to determine whether the estimated contrast of parameter estimates was significantly different from zero.

Separate repeated-measures ANOVAs were performed on the behavioral data to investigate the independent effects of boundariness and color complexity on various performance measures. We will consider first the effect of boundariness, our manipulation of interest. There were five levels zero walls to four walls.

Accuracy in identifying whether the test image was consistent with the imagined scene was scored on a four-point scale in which correct and incorrect responses were weighted by confidence: 1, high confident correct response; 2, low confident correct response; 3, low confident incorrect response; 4, high confident incorrect response Table 1.

Mean accuracy scores for the different experimental conditions SEMs are shown in parentheses. Accuracy scores are correct and incorrect responses weighted by confidence see Results. Perfect score is 1, range of 1—4. The other experimental manipulation was of the color complexity of the environmental features. There were four levels of color complexity see Materials and Methods. However, preliminary analyses revealed that there were no behavioral measures that differentiated the middle two levels, which comprised either separately colored environmental elements or environmental elements with long strips of a single color Fig.

The relationship between boundariness, color complexity, and postscan ratings of difficulty to imagine is shown in Figure 3. Behavioral results. The relationship between perceived difficulty of imagining the different scenes, the number of boundaries, and color condition. In summary, the fact that the relationship between measures of task difficulty and the number of boundaries followed an inverted U-shape indicates that any observed parametric fMRI responses related to increased numbers of boundaries could not simply reflect task difficulty.

The orthogonal manipulation of color complexity had a linear effect on most measures of task difficulty, and there were no systematic interactions between color complexity and the levels of boundariness on difficulty. Initial analyses identified a network of brain regions recruited during the imagination and encoding phases that are consistent with previous neuroimaging studies of spatial memory Burgess et al.

Similar activations were found for the structures as for the scenes. Our main hypothesis was that the hippocampus will be more engaged when imagining scenes containing more enclosing boundaries. To test this, the critical analysis involved identifying brain regions in which the BOLD response varies parametrically with boundariness. The results are shown in Figure 4.

These regions all show positive correlations between the number of boundaries and BOLD response: the more boundaries there were in the imagined environment, the higher the activation. Boundary-related activation. There was a parametric modulation of BOLD response by the number of boundaries in four brain regions, including the middle of the left hippocampus.

These are shown in the glass brain A. The percentage signal change in the hippocampus for the five levels of boundary are shown in B. The hippocampal activation is shown projected on to the mean structural image in the top row of C , and the other activations are shown in the bottom row color bar indicates t -statistic. D shows the percentage signal change associated with the parametric modulation of BOLD by the number of boundaries for the four regions all trials and trials split by high and low vividness ratings.

Brain regions showing a significant parametric modulation of BOLD response by the number of boundaries in the imagined environments. L, Left; R, right. Top, All trials; bottom, vividly imagined trials only. According to the model of Burgess and colleagues Byrne et al, , the hippocampus is necessary to generate imagery for spatially coherent scenes with respect to environmental boundaries. It follows that the boundary effect should be clearest during successful generation of internal images, i.

For this reason, responses were classed as high vividness response 1 or low vividness responses 2—4. We first investigated the boundary effect in the four regions identified in the previous analysis. In all regions apart from the lateral parietal area on the right, the parametric boundary effect was stronger and less variable for more vividly imagined scenes Fig. In the lateral parietal region, the effect appeared to be as strong for less vivid scenes but far more variable across subjects.

Additionally, there was again activation of the medial parietal lobe. There were also regions of activations in the left anterior insula and the frontal cortex Table 2 , bottom. Boundary-related activation during the high vividness trials color bar indicates t -statistic. We looked for activations that showed significant correlations with boundariness during encoding.

There were bilateral activations in frontal cortex as well as the insula bilaterally, left-sided middle temporal gyrus, posterior cingulate, and lateral parietal lobe angular and supramarginal gyrus supplemental Table 3, available at www. However, the parametric boundary effect was not present in the hippocampus at encoding.

This analysis provides some evidence that the boundary effect was present in the hippocampus while encoding the to-be-imagined images, but the effect was considerably weaker than during the imagination phase itself. As a nonspatial control for the boundary analysis, we looked for activations showing a parametric effect of increasing color complexity. This manipulation had an effect on accuracy and ratings of difficulty to imagine see above , indicating that it increased the complexity of the environmental features that had to be imagined.

During imagination, activations varying parametrically with increasing color complexity were found in the right hemisphere in the inferior and middle frontal gyri, the inferior temporal gyrus, and bilaterally in the cerebellum supplemental Table 4, available at www. During encoding, there were extensive regions of occipital cortex in which activity correlated with increasing color complexity supplemental Table 5, available at www.

These results demonstrate that hippocampal activity is not always modulated by manipulation of aspects of the to-be-imagined scenes. Varying the color complexity of the elements in the scenes had an impact on behavioral measures of task difficulty but only a weak and nonsignificant impact on hippocampal activation. Although the hippocampus was insensitive to a nonspatial manipulation of environmental complexity, it is possible that hippocampal activity might reflect the fact that some boundary conditions were more difficult to imagine than others.

The relationship between the ability to match the test image with the imagined scene and number of boundaries was U-shaped, meaning that scenes that contained approximately equal numbers of walls and towers were most difficult to visualize Table 1. In this analysis, we looked for activity that correlated with increasing boundary-related task difficulty. The accuracy scores were used to calculate difficulty parameters corresponding to the five boundary levels Table 1 , Combined.

Robust correlations were found in superior lateral and medial parietal regions and premotor cortex supplemental Table 6, available at www. This analysis demonstrates that the boundary effect is not caused by how difficult the different layouts of boundaries were to imagine. In a final analysis of task difficulty effects, we investigated which areas showed BOLD correlations with postscan ratings of how difficult the environments were to visualize. This analysis revealed a network of regions very similar to the one identified with boundary-related task difficulty supplemental Table 7, available at www.

Once again, this shows that the boundary effect is not driven by task difficulty. Participants visualized standing in environments that contained varying proportions of colored walls boundaries and towers nonboundaries. Hippocampal activity increased with increasing numbers of environmental boundaries in the scenes the boundary effect , particularly those that were vividly imagined.

In contrast, hippocampal activity was not significantly modulated by increasing color complexity of the environments or by levels of difficulty. These findings are consistent with the hippocampus playing a similar role when orienting oneself in an imagined space as place cells play when animals orient themselves in real space O'Keefe and Burgess, ; Hartley et al. Our sense of location is likely supported by the firing of hippocampal place cells O'Keefe and Nadel, ; Ekstrom et al.

We have proposed that the same machinery required to orient oneself in the physical world also supports mental imagery of spatially coherent environments: reciprocal connections between place cells, BVCs, and representations of objects enable reactivation of the contents of a scene, consistent with perception from a single location within an environment Becker and Burgess, ; Burgess et al. Doeller et al. Consistent with this, increasing the number of boundaries which is directly related to their horizontal extent in an imagined scene parametrically increased BOLD response in a region of the left hippocampus Fig.

Importantly, the boundary effect was only present in the hippocampus during vividly imagined trials, consistent with a dependence on what is actually visualized rather than the aim of visualization. Furthermore, the effect was only reliably found during imagination; merely attending to images of scenes containing more boundaries did not modulate hippocampal activation.

We suggest that the subthreshold trend for a boundary-related effect while encoding scenes reflects participants starting to visualize the scene. Distortions to the boundaries in a virtual-reality environment cause biases in human object location memory that mimic distortions in hippocampal place fields Hartley et al. Based on the influence of environmental features on place cell firing, we have conceptualized anything that extends horizontally and impedes motion across it as a boundary [i.

Nevertheless, through inspection of Figure 4 , it appears that the largest increase in hippocampal activation corresponds to the change from no boundaries to one. Although the model predicts increasing hippocampal involvement with increasing numbers of enclosing boundaries, it may be that the addition of the first boundary relative to none increases activation more than subsequent additions.

This may relate to the recent finding that imagining the first object in a scene increases activation in the left medial temporal lobe, whereas the addition of subsequent objects has a more variable effect Summerfield et al. Our study specifically investigated parametric boundary-related effects on BOLD activity during imagination rather than regions associated with imagination per se, and the regions identified with the boundary effect are only a subset of the core network.

One, the precuneus, has been hypothesized to maintain an egocentric representation of the scene elements that are visible from a particular location Becker and Burgess, ; Burgess et al. Consistent with this role, the precuneus is activated when participants are required to visualize a third-person perspective Vogeley et al. The presence of the boundary effect in the precuneus suggests that neurons in this region can be driven by medial temporal lobe representations of environmental boundaries supported by place cells and BVCs.

This suggests that it responds to the spatial layout of scenes regardless of their structural elements. The BVC model predicted that cells responding to environmental boundaries would be found in regions inputting to the hippocampus, and such cells have been described recently in rodent subiculum and entorhinal cortex Savelli et al. Why then did these regions not show a boundary effect?

According to the model, the relatively large number of place cells receive inputs from different combinations of a much smaller number of BVCs. Thus, it may be that the hippocampal place cells produce a stronger fMRI signal than the more sparse populations of BVCs themselves. The left lateralization of the boundary effect is apparently at odds with neuropsychological evidence that visuospatial processing in the medial temporal lobe is right lateralized Milner, ; Frisk and Milner, However, increasing correlations with detail in imagined or recollected episodes have been reported in the left hippocampus Addis et al.

The hippocampus is necessary for remembering spatial and relational information over short delays Hannula et al. However, our nonspatial manipulation of the color complexity of the imagined environments did not modulate hippocampal activation, nor did scenes that were rated more difficult to imagine supplemental Fig.

Similarly, hippocampal activation did not reflect the difficulty of imaging the different spatial layouts used as evidenced by performance on the memory task. In contrast, a network of parietal and frontal regions supplemental Tables 6, 7, available at www. We have specifically focused on the role of the hippocampus in representing environmental geometry, but the hippocampus will clearly also make other contributions to imagination more generally. Other imagination studies have described hippocampal activations modulated by the decreasing probability that an event will occur and by the increasing remoteness of a future event Addis and Schacter, ; Weiler et al.

Both of these studies proposed that less likely and more remote events require greater relational processing. Using a very different paradigm, Andrews-Hanna et al. Another key component of these tasks is the linking together of a sequence of events that happens within the spatial context.

In addition, it has been suggested that grid cells Hafting et al. These studies demonstrate the broad potential of mapping between neuronal representations in rodents to mechanisms of human episodic memory, imagination, and future thinking Buckner, and illustrate the potential range of functional contributions that might be supported by the hippocampal formation.

We have identified a specific role for the hippocampus in mental imagery for scenes: constructing scenes so as to be spatially coherent with respect to environmental boundaries. In contrast, there was no evidence that hippocampal involvement in mental imagery is modulated by either nonspatial complexity of the scenes or increasingly complex configurations of environmental features.

When navigating in the world, the hippocampus is involved in computing one's location with respect to environmental boundaries both within and outside of the current field of view. Persons with factor H deficiency have a predilection for developing renal disease Excessive complement activation because of complete deficiency of factor H, or because of mutations or autoantibodies that that result in loss of complement-inhibiting functions of factor H, leads to uninhibited complement activation and the development of type II membranoproliferative glomerulonephritis MPGN II In the absence of factor I, there will not be any processing of C3b to iC3b or C3d.

Using mice that were deficient in either factor H alone, factor I alone, or both factors H and I, Rose et al. The clinical manifestations and pathophysiology of renal disease in factor H deficiency have been reviewed by Pickering and Cook The genetic control of MBL levels is described above. The MBL level in each individual remains fairly stable throughout life.

At birth, concentrations are two-thirds of adult levels, which are reached in a month, and there is a minor decline in old age Studies that address the correlation of MBL levels with infections must be interpreted with caution. Second, the finding that MBL levels were genetically determined led to several investigators using allotyping to correlate MBL levels with disease. While such studies have yielded useful insights, it must be noted that the MBL levels in individuals with the identical genotype for all MBL variants may differ by as much as fold The problems surrounding the interpretation of the role of MBL in clinical studies have been aptly summed up by Jensenius et al.

Very little variation is seen in samples withdrawn over 1 year, but elevated MBL concentrations are observed during infections or after major operations with increases of up to 3-fold. Possibly this relatively small compared with fold steady-state interindividual differences acute-phase response has prompted investigators to base their investigations solely on allotypes analyses—and, sadly to say, in most cases they are only encompassing the structural allotypes.

The reliance on structural allotypes will, everything else being equal, be expected to result in finding a lower than the true significance of the MBL association with whatever is being investigated. Just prior to the discovery of MBL, Soothill and Harvey found that the sera from 11 of 43 children with recurrent infections did not support opsonization of Saccharomyces cerevisiae baker's yeast.

These children commonly had infections of the skin and respiratory tract, with rare involvement of the bone, and S. Other pathogens isolated included S. About half of the patients had generalized rash and diarrhea. A similar defect in opsonization was seen in 4 of 72 healthy adults and 1 of 11 children with unrelated diseases, which was significantly lower than the incidence in the study population. The defect was not attributed to Ig deficiencies or lack of hemolytic activity but was corrected by normal serum.

The same group reported defective yeast opsonization in four children with protracted diarrhea; plasma infusions corrected the opsonization defect in all four and resulted in symptomatic improvement in three children Subsequently, Super et al. These individuals had low MBL levels, and the opsonization defect was corrected by purified MBL in a dose-dependent fashion in an assay that measured the deposition of complement on a mannan-coated surface.

Sumiya et al. These early studies spurred a burst of investigations that attempted to define the association between MBL deficiency and susceptibility to infections. The range of infections in four persons with MBL exon 1 genotype defects and one person with a combined MBL and IgA deficiency, whose ages ranged from 15 to 56 years, included recurrent skin abscesses, chronic cryptosporidial diarrhea, meningococcal meningitis with recurrent herpes simplex, and fatal lobar pneumonia due to Klebsiella Kakkanaiah et al.

A second study group consisted of 73 pediatric and 56 adult patients with recurrent infections. Pediatric patients had significantly lower mean concentrations of serum MBL than their healthy controls. These results provide evidence that low concentrations of serum MBL are associated with recurrent infections not only in children but also in adults.

Consistent with the wide array of infections reported in persons with MBL deficiency, several in vitro studies have demonstrated that MBL binds to a diverse spectrum of pathogens and that bound MBL can promote C4 deposition on the pathogen surface , , , , , , Such studies have prompted investigators to link MBL deficiency with infections, and this is discussed next. Because of the importance of complement in host defenses against meningococcal infections, the interactions of MBL with N.

Case reports and studies of individual families have suggested an association between low MBL levels and meningococcal disease 23 , , A study of a Danish family suggested that the combination of MBL and properdin deficiencies may heighten the predisposition to meningococcal disease. Four members of this family suffered meningococcal disease, and one case was fatal. Two of six males with undetectable properdin levels had meningitis, and both these patients had MBL variant alleles that predicted low MBL levels.

High MBL concentrations were seen in three of the remaining four properdin-deficient males, and none had meningitis Population-based studies substantiate a role for MBL in defenses against meningococcal disease. The frequency of variants of the MBL gene in children in the United Kingdom with meningococcal disease versus controls was ascertained in two independent studies. One study was hospital based patients and control patients with noninfectious disorders , and the other was community based 72 patients and control healthy individuals.

The proportion of homozygosity for MBL variant alleles was higher in patients with meningococcal disease than in controls in both the hospital study 7. A key difference in the two studies was that the mean age in the United Kingdom hospital cohort was 3. More recently, mutations in exon 1 of mbl2 that determine low MBL levels codons 54, 52, and 57 were examined in a pediatric cohort ages 2 to months with invasive meningococcal disease and compared to those in healthy age-matched volunteers with no history of meningococcal disease The overall frequency of an MBL exon 1 variant genotype was significantly higher in patients than in controls When stratified according to age, This was further increased and most pronounced in children with disease onset at less than 12 months of age Clinical severity and outcome did not differ between patients with wild-type and mutant alleles Collectively, these data support the notion that MBL plays an important role in protection against disease in early childhood prior to maturation of the adaptive immune system A case-control study in Oxfordshire, England, found a 2.

Invasive infections with S. Impaired recognition of GlcNAc may have predisposed patients homozygous for MBL mutations to type 14 pneumococcal disease. However, another study of patients with invasive pneumococcal infections in Denmark did not find a statistically significant increased risk for MBL polymorphisms The different conclusions may relate to the very low prevalence of homozygous MBL mutations in the latter study, a reflection of the smaller number of participants.

Similarly, a small study of 63 Belgian patients with invasive pneumococcal disease found an increased, albeit statistically insignificant, association with MBL structural codon 54, 52, and 57 polymorphisms. The authors of this study stated that combining their data with the study by Kronberg et al. Eisen et al. Taking the data together, it could be concluded that while MBL deficiency may not be a risk factor for developing pneumococcal infection, persons with homozygous variant MBL alleles may have an increased risk of death from invasive pneumococcal disease.

The high frequency of variant MBL alleles that result in low MBL levels in populations with a high prevalence of tuberculosis has raised speculation that low MBL levels may protect these individuals against disease. MBL binds to lipoarabinomannan LAM on the mycobacterial surface , which is also a mycobacterial ligand for mannose receptors on monocytes and macrophages.

Low levels of MBL that result in limited complement activation but that are sufficient to bind to LAM and block engagement of mannose receptors may be most beneficial for the host. This, however, is likely to be an oversimplified hypothesis, because MBL itself can bind to CR1 and could enhance bacterial uptake. Further, MBL bound to bacteria could affect ligation of macrophage receptors, which can modulate the release of cytokines such as IL that play a critical role in host responses to infection A few studies have evaluated the association between MBL polymorphisms and malaria.

The higher frequency of low-MBL-determining genotypes in regions where malaria is endemic raises the possibility that this disease could be a selection factor for variant MBL genes. In a matched case-control study with Ghanaian children, the influence of six polymorphisms of the mbl2 gene on P. In a study of Gabonese children, increased MBL plasma levels and corresponding mbl2 genotypes were associated with lower concentrations of several cytokines and chemokines in plasma specimens from malaria patients Another study of MBL levels and polymorphisms in Gabonese children participating in a prospective study of severe and mild malaria due to infection with P.

These results suggest that compromised innate immune responses in the form of low MBL levels may be a risk factor for severe malaria in young children who lack mature acquired immune responses. The studies examining the MBL genotypes or levels with hepatitis B and C disease progression or complications have been summarized in a recent review by Brown et al.

Disease progression is likely to be multifactorial and influenced by several factors, including ethnicity, alcohol consumption, concomitant infections, and HLA alleles. Several studies address only the mbl2 genotype and in some cases only selected genotypes without a measurement of serum MBL levels.

Despite the differences in cohort characteristics and MBL genotypes studied, there appears to be a correlation between low-MBL-producing genotypes and hepatitis B disease progression. Such data raise the possibility that MBL levels could play a role in the susceptibility to or clinical course of HIV infection.

On the other hand, data linking MBL levels with disease progression are conflicting. The rate of disease progression is often determined by coinfection with other pathogens, and the interactions of MBL with these coinfecting pathogens may confound interpretation of the data.

As an example, high MBL levels may predispose individuals to tuberculosis. With the advent of better antiretroviral therapy and longer life expectancy of HIV-infected individuals in resource-sufficient settings, additional studies that examine the role of MBL in disease progression may be warranted. Because mannan is an important component of fungal cell walls, the possible role of MBL in fungal infections has been investigated. Belgian women suffering from recurrent vulvovaginal candidiasis were more likely to possess the variant mbl2 codon 54 allele B than control women 20 versus 6.

Those authors also reported that the presence of the B allele was associated with significantly fewer recurrences among women who were placed on chronic fluconazole maintenance therapy. Carriage of MBL allele B was also more frequent in Brazilian women with recurrent vulvovaginal candidiasis MBL concentrations in cervicovaginal lavage fluid specimens from Chinese and Latvian 17 , 18 women with recurrent vulvovaginal candidiasis were lower than those in a control population.

Interestingly, women with acute vulvovaginal candidiasis had higher local MBL levels than control women , possibly a reflection of the fact that MBL is an acute-phase reactant. In contrast, a study on Italian women did not show any increase in the rates of vulvovaginal candidiasis and MBL exon 1 mutations MBL may also have a protective role in deep-seated Candida infections.

Patients with positive intra-abdominal yeast cultures had significantly lower MBL levels than did patients with negative cultures median of 0. A recent study compared MBL levels between 65 adult patients with proven or probable invasive aspergillosis and 78 immunocompromised control subjects with a febrile illness.

Another form of pulmonary aspergillosis is called allergic bronchopulmonary aspergillosis ABPA. Studies of Indians with ABPA have shown that the A allele in intron 1 was associated with higher MBL levels and higher levels of circulating eosinophils and IgE, the latter two being associated with disease severity , Cystic fibrosis CF is a hereditary disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator CFTR gene and affects the exocrine glands of the lungs, liver, pancreas, and intestines.

Pulmonary infections are a major cause of morbidity in CF. Younger children become infected with bacteria such as H. A study of CF patients showed that lung function was significantly impaired in carriers of MBL variant alleles compared to normal homozygotes However, among those children colonized with P. Why children with lower MBL levels are more predisposed to lung damage following colonization with P.

The correlation between severity of lung disease in CF patients and low MBL alleles was confirmed in a subsequent study Again, MBL sufficiency did not offer protection against colonization with P. Davies et al. Other studies, however, did not report an association between MBL levels and disease severity in CF 53 , In a large study of 1, Canadian CF patients, Dorfman et al.

Although inherited deficiencies of ficolins are rare, polymorphisms that influence the concentration and function of ficolin-2 L-ficolin have been described In a recent study, Munthe-Fog et al. Heterozygous individuals had about half the ficolin-3 levels seen in control normal individuals.

The homozygous individual was a year-old man who had unrelated parents of Macedonian and Albanian origin. He suffered multiple lower respiratory tract infections since early childhood and also had recurrent warts in his fingers. At the age of 20 he underwent a splenectomy for thrombocytopenia. At 26 years of age he had cerebral abscesses caused by nonhemolytic streptococci. Following this, he had multiple episodes of bacterial pneumonia, and sputum cultures yielded H.

The patient had no measurable ficolin-3 levels and, as expected, no ability to activate C4 through ficolin-3 C3 occupies a central position in the complement cascade and subserves several critical functions, which include solubilization of immune complexes, enhancing bacterial killing either through membrane attack complex formation or opsonophagocytosis, and potentiation of the humoral immune response.

About 20 families with total C3 deficiency inherited in an autosomal recessive manner have been described , Not surprisingly, C3-deficient individuals develop autoimmune disorders, infections, or both. Infections tend to be recurrent and severe. Invasive infections meningitis, bacteremia, pneumonia, and otitis media with S. Because of its role in bridging innate immunity and adaptive immunity, persons with C3 deficiency show impaired responses to immunization.

Immunization of a 2-year-old child with total C3 deficiency and a history of recurrent pyogenic infections did not induce a long-term antibody response Maturation of dendritic cells was impaired, with decreased CD1a expression and ILp70 secretion ability. These cells were unable to induce autologous B cell proliferation and Ig secretion in the presence of CD40 ligand and C3. Thus, various aspects of the adaptive immune responses are impaired in C3 deficiency.

C3 deficiency can also result from excessive activation and consumption of complement. Such a situation arises with deficiencies of factor H or factor I or in the presence of C3 nephritic factor, as discussed above. However, the presence of even small amounts of C3 reduces the severity and frequency of infections. Invasive meningococcal disease and disseminated gonococcal infection DGI are the only conditions known to be associated with deficiencies of the terminal components of complement C5 through C9.

All late complement deficiencies are inherited in an autosomal recessive manner; heterozygous individuals usually express about half of the normal levels of the protein. While polymorphisms of terminal complement components have been described, their clinical significance is not clear.

Nonsense mutations were responsible for C5 deficiency in two African-American families Homozygosity for double mutation in exon 40 of the C5 gene caused missense and frameshift mutations that resulted in production of a truncated and highly unstable C5 molecule in a Spanish family One member of this family suffered from meningococcal sepsis and several episodes of pneumonia, and a second person had bacterial meningitis twice and frequent episodes of tonsillitis, pneumonia, and herpes.

C5 deficiency secondary to a point mutation in exon 10 was identified in a 5-year-old Turkish boy with two episodes of bacterial meningitis N. An important distinction between C5 deficiency and deficiency of the other components of the terminal complement pathway is that C5-deficient patients lack the ability to mount an efficient chemotactic response because of the absence of C5a generation. While much attention has been focused on the high incidence of meningococcal disease in terminal-complement-deficient persons, there may also be increased susceptibility to disseminated gonococcal infection.

The case report of a C5-deficient male with nine episodes of DGI is illustrative. C6 deficiency is usually the result of point mutations, and some of these have been identified in Japanese, mixed-race South African, African-American, Dutch, and Irish populations , , , The result is a truncated polypeptide that is There have been no reported instances of meningococcal disease in any of the 10 individuals identified with subtotal C6 deficiency, suggesting that even a small amount of lytic activity in serum may be sufficient to alleviate the high risk of meningococcal disease seen with total deficiency of terminal complement components.

Subtotal C6 deficiency in combination with subtotal C7 deficiency has been reported in two families The same mutation was found in a Russian patient who had two episodes of meningococcal disease as a child. This patient also had chronic otitis media that was only partially responsive to medical treatment; S.

The highest prevalence of homozygous C9 deficiency , is seen in the Japanese population. These data were obtained from large-scale screening of blood donors or hospitalized patients , , Most deficiencies result from point mutations that result in premature stop codons C9 deficiency is very rare in other populations. Serum from C9-deficient individuals can support complement-dependent hemolysis of antibody-sensitized erythrocytes , although the reaction is times slower than with C9-sufficient serum.

Similarly, a serum-sensitive strain of E. Killing of a serum-sensitive strain of N. Interestingly, the risks of meningococcal disease among C7- and C9-deficient persons in the Japanese population were approximately 10, and 1,fold higher than that in complement-sufficient controls These data strongly support the notion that the predisposition to meningococcal disease is strongly linked to the efficiency of complement-dependent bactericidal activity.

LAD-1 is an autosomal recessive condition that can result from one of several different described mutations. This disorder is characterized by prolonged and recurrent infections, often with Staphylococcus and Pseudomonas , that begin in infancy. A history of delayed separation and infection of the umbilical cord omphalitis may be present. Infections of the soft tissues, mucosal surfaces, and intestines, often with extensive necrosis, can occur.

Mortality is high, and about half of affected individuals die before 2 years of age. Acute gingivitis is almost universally seen in individuals who reach childhood. Because of defective adhesion of leukocytes to endothelium that results in defective margination, there is a persistent leukocytosis 2 to 20 times the normal despite the absence of any active infection. Disease severity is inversely proportional to the amount of CD18 expression.

The success of a pathogen lies in its ability to evade host immune defenses. It should be emphasized that although most studies of complement-microbe interactions have been carried out with serum, complement components are present even at mucosal surfaces and in almost every body fluid studied. About 50 years ago, Roantree and Rantz showed that Gram-negative bacteria isolated from the bloodstream were almost always resistant to complement-dependent bactericidal activity, underscoring the importance of complement evasion in bacterial pathogenesis While Gram-negative bacteria can potentially be killed by complement alone by insertion of the membrane attack complex, Gram-positive bacteria and fungi are intrinsically resistant to the lytic activity of complement because they possess thick cell walls.

However, complement deposition on gram-positive bacteria and fungi results in deposition of C3 fragments that act as opsonins. Activation of C5 results in generation of C5a, a potent chemotaxin that recruits polymorphonuclear leukocytes to facilitate phagocytosis. Limiting C3 deposition would therefore confer an advantage to microbes by dampening inflammation.

On the other hand, certain intracellular microbes, such as M. Over the past 3 decades, numerous microbial complement evasion strategies have been elucidated. There are examples of microbes that block complement activation at every step , , The presence of more than one complement evasion mechanism concomitantly has been described for several pathogens; in fact, the presence of multiple complement-dampening strategies appears to be the rule rather than the exception.

A detailed review of microbial complement evasion mechanisms is beyond the scope of this review, and only a few examples are provided here. Every microbe activates the complement system; however, the degree of complement activation varies among organisms. Effective insertion of C5b-9 into the bacterial membrane requires complement activation and C5 convertase formation close to the bacterial membrane.

The chemical composition of the O antigenic repeats in Salmonella determines the rate of alternative pathway activation and initial C3b binding as well as amplification of initially deposited C3b by the alternative pathway positive feedback loop A critical density of long LPS molecules in Salmonella enterica serovar Montevideo was required to sterically hinder access of C5b-9 to the outer membrane The presence of O-antigenic repeats could also interfere with assembly and insertion of the terminal complement pathway.

Incorporation of C8 and C9 into the stably bound C5b-7 complex caused release of the entire complex from the bacterial surface of a smooth-LPS-bearing strain of S. Capsular polysaccharides play a key role in pathogenesis of a wide array of bacteria and fungi.

Capsules are antiphagocytic and often limit complement activation. Capsules have diverse chemical structures, but in most instances they are polyanionic. Despite their ubiquitous presence, surprisingly little is known about the mechanism s by which they regulate complement. Sialic acid-containing capsules have received considerable attention, probably because the role of sialic acids in regulating the alternative pathway on erythrocytes has been well studied.

The capsule of type III group B streptococci regulates the alternative pathway; removal of the terminal sialic acid residues by neuraminidase treatment converts the bacterium from a nonactivator to an activator of the alternative pathway , Desialylation of N. Sialic acid is used as a virulence factor by several microorganisms.

The ability of Sindbis virus to activate the alternative pathway of complement is inversely related to its host-determined envelope sialic acid content Desialylation of the trypomastigotes results in an increased ratio of C3b to the inactive molecule, iC3b, and results in increased lysis of the organism The LPSs of several gram-negative bacteria, including H.

Capsular polysaccharide expression appears to be important for high-level serum resistance in H. In contrast, nontypeable H. Bacteria that elaborate LOS have evolved sophisticated mechanisms to escape complement. Incorporation of sialic acid onto LOS is a mechanism shared by several strains of N.

Sialoglycans on erythrocytes regulate the alternative pathway by virtue of their ability to enhance the interactions of factor H with C3b while simultaneously decreasing factor B-C3b interactions ; it is presumed that LOS sialic acid regulates the alternative pathway by a similar mechanism.

Effective complement activation on bacteria such as H. In the absence of specific antibody, the alternative and MBL pathways cannot support bactericidal activity of serum, which may contribute to the higher incidence of disease with H. Colonization is an immunizing process ; the development of a repertoire of protective antibodies with age as a result of colonization may be associated with decreased disease rates in older children and adults.

Although the MBL pathway alone does not mediate bactericidal activity in vitro , it may play an important role prior to the development of antibodies by functioning as an opsonin. As discussed above, MBL deficiencies are associated with a wide range of infections. Over the past decade, binding of complement inhibitors such as C1 inhibitor, factor H, factor H-like protein-1 FHL-1 an alternatively spliced variant of factor H that also has complement inhibiting function , C4b-binding protein C4BP , and vitronectin to several bacteria, fungi, viruses, and parasites has been described Binding of complement inhibitors is associated with complement inhibition on the bacterial surface.

Certain members of the pox- and herpesvirus families have proven to be particularly adept at expressing molecules that mimic the function of host complement inhibitors. Cells infected with vaccinia virus secrete a virus-encoded protein called the vaccine virus complement control protein VCP that resembles part of the human C4BP molecule and can inhibit the classical and alternative pathways. Similarly, Kaposi's sarcoma-associated herpesvirus KSHV expresses a complement-downregulatory protein that is organized into domains characteristic of complement inhibitors such as factor H and C4BP , Several bacteria secrete proteases that degrade complement components or molecules that interfere with complement activation.

These include P. This bacterium expresses or secretes numerous proteins that can block complement activation at almost every step of the cascade in an effort to reduce chemotaxin production by the host , While development of an antibody response in most instances is protective, it can sometimes decrease killing by otherwise bactericidal serum and enhance the susceptibility to infection. Antibodies that develop at a later stage of Brucella abortus infection were shown to block the bactericidal effects of antibodies that developed early following infection Some patients with chronic urinary tract infections with E.

Blocking antibodies may play an important role in neisserial infections. Sera from patients convalescing from meningococcal infection are sometimes less effective at killing meningococci than sera collected during the acute phase of infection. These sera can block killing by otherwise bactericidal normal human sera , IgA purified from human serum following infection with group B, C, and Y meningococci blocked complement-mediated bacteriolysis by the same sera In a separate study, sera from 24 of 28 military recruits with meningococcal disease lacked bactericidal activity; removal of IgA from these 24 sera uniformly enhanced the bactericidal activity of IgM present in the same sera IgA1 directed against N.

Blocking antibody plays an important role in the pathogenesis of N. In a longitudinal study of female commercial sex workers who experienced frequent gonococcal infection, those with antibody to reduction modifiable protein Rmp; protein III were at increased risk of infection adjusted odds ratio, 3. Immunopurification studies confirmed the specificity of the gonococcal target for blocking antibodies as Rmp Because of the high prevalence and recurrent nature of meningococcal disease in complement-deficient persons, a discussion of its pathogenesis and interactions with the complement system is merited.

Disseminated gonococcal infection DGI has also been reported in persons with complement deficiencies; probably the most spectacular case was that of a person with nine episodes of DGI However, given the high frequency of transmission of gonorrhea among sexual contacts and the strong association between certain auxotypes and phenotypes including the ability to resist complement of N. Figueroa and Densen have made several seminal observations regarding the characteristics of meningococcal infection in complement-deficient patients based upon comprehensive cataloging of cases reported prior to The results of their findings are summarized below, in addition to newer data obtained since their review.

Meningococci have been classified into 13 serogroups based upon the chemical composition of their capsular polysaccharides 74 , , These epidemics have led to the development and deployment of strain-specific outer membrane vesicle vaccines Serogroup C causes smaller-scale outbreaks worldwide. Over the past 2 decades the incidence of serogroup Y disease in the United States has climbed, and it now accounts for a third of cases , Serogroup W strains were responsible for a large outbreak among pilgrims to the Hajj in Saudi Arabia in and and for an epidemic in Burkina Faso in More recently, epidemics of serogroup X disease have been reported in Africa 95 , While it is well established that inherited deficiencies of complement constitute a strong risk factor for meningococcal disease, the risk of meningococcal disease in persons with acquired complement defects is less clear.

The complement profiles of two patients with severe hepatic failure that was complicated with meningococcemia were studied by Ellison et al. Of 20 patients presenting with their first episode of invasive meningococcal disease, 6 had a CH50 level of less than 2 standard deviations below the normal mean Of these patients, two had inherited C6 deficiency and one had inherited C8 deficiency.

The remaining three had defects in multiple complement components associated with SLE or multiple myeloma. Garty et al. The latter two patients had low C3, C4, and CH50 levels prior to the onset of infection. The concomitant occurrence of these two rare entities supported an association between acquired complement deficiencies and meningococcal disease. Reports by Feliciano et al. Hypocomplementemia as a result of C3 NeF has also been associated with meningococcal disease A case of meningococcal disease in a patient with transient complement deficiency caused by poststreptococcal glomerulonephritis has been reported Collectively, the evidence suggests that individuals with acquired complement defects secondary to complement consumption states are at a higher risk for developing invasive neisserial disease.

As discussed above, the incidence of hereditary deficiencies of complement components varies widely depending on the complement protein and the population studied. This contrasts with the low frequency 0. In contrast, C7 deficiency was relatively common in the Israeli Moroccan Jewish population; of a total of healthy blood donors, 1 0.

A relatively high frequency of C6 deficiency has been detected in the western Cape population of South Africa , The association of complement deficiencies with invasive neisserial infections prompted several studies to estimate the frequency of complement deficiencies among patients with their first episode of systemic neisserial infection 24 , 80 , 94 , , , , , , , , , , , Figueroa and Densen plotted the incidence of complement deficiency detected in patients with meningococcal disease versus the incidence of meningococcal disease in the general population and showed that the rate of complement deficiencies detected dropped in areas where the incidence of disease was high.

The introduction of a hypervirulent clone into a nonimmune population would result in disease and spread of the strain efficiently among normal as well as complement-deficient individuals, and because the number of the former greatly exceeds the number of the latter, the relative proportion of complement-deficient persons affected will be small.

In nonepidemic situations or when the population at large has developed immunity against the prevalent strain, the complement-deficient individuals are likely to be at a higher risk and would represent a greater proportion of cases. Nasopharyngeal colonization is the first step in meningococcal pathogenesis. Humans are the only known reservoirs for N. Type IV pili are crucial for attachment of meningococci to epithelial cells. Encapsulated meningococci possess a highly negatively charged capsule which can interfere with the engagement of several bacterial adhesins with their cellular receptors.

Type IV pili are polymeric filamentous proteins that protrude beyond the capsule and are instrumental in mediating initial attachment of bacteria to cells. Pili undergo extensive antigenic variation that regulates adhesion of bacteria to cells. Some pilus variants form bundles of pili that bind bacteria together and allow them to grow as microcolonies on the cell surface. Following the initial attachment, more intimate attachment occurs through other bacterial molecules, including opacity protein Opa , neisserial adhesin A NadA , and lipooligosaccharide LOS.

Mechanisms of adherence and invasion have been discussed by Virji and Nassif et al. Capsular polysaccharide is the most important N. With a few exceptions , , , almost every reported case of invasive disease is caused by encapsulated organisms. Capsular polysaccharide expression increases the resistance of bacteria to complement-dependent killing.

The exact mechanism by which the various capsular polysaccharides confer serum resistance is not clear. A majority of invasive meningococcal isolates express the sialylated lacto- N -neotetraose LOS species , Neisserial LOS molecules mimic host carbohydrates , , which could contribute to the ability to evade host immunity. In contrast, carrier strains isolated from the nasopharynx tend to express LOS species that cannot be sialylated These observations support a role for LOS sialic acid in pathogenesis of invasive disease.

However, the role for LOS sialylation in mediating serum resistance in meningococci is not as clearly defined as for N. Another membrane component that plays a role in enhancing meningococcal serum resistance is called factor H-binding protein fHbp.

Bernfield, L. Fletcher, A. Howell, J. Farley, R. Zagursky, M. Knauf, and G. While all meningococcal strains isolated to date express fHbp, expression levels vary widely across strains The role of blocking antibodies directed against capsule has been discussed above as part of the discussion of bacterial complement evasion strategies. Considering the high rates of carriage, the incidence of invasive meningococcal disease, even during epidemics, is relatively low.

Unencapsulated strains adhere more efficiently to nasopharyngeal epithelial cells and may therefore have an advantage over encapsulated strains in their ability to establish colonization. The seminal studies of Goldschneider et al. The percentage of sera that lacked bactericidal activity reached a nadir in samples from children between 6 months and 2 years of age, which coincided with the age of maximum susceptibility to disease.

In the next set of experiments, baseline serum samples were collected from army recruits at Fort Dix at their time of enrollment and from recruits who contracted meningococcal disease. Serum bactericidal assays were performed against the group C strain that caused an epidemic in the camp using the baseline sera from 54 patients and controls; only 3 of 54 5.

The baseline sera from patients also did not kill heterologous strains; bactericidal titers of or greater against a group A, B, or C strain were seen with only To better understand the dynamics of colonization and invasion, sera from recruits were obtained at baseline and nasopharyngeal swabs were taken at 2-week intervals over an 8-week period. Of these 54 potentially susceptible individuals, 44 were colonized with meningococci over the 8-week period; 24 of the 44 isolates were group C the epidemic was also caused by a group C strain.

However, 11 recruits had bactericidal titers against their colonizing group C strain, which suggested that this group C strain was distinct from the epidemic strain. Of the remaining 13 recruits, 5 suffered invasive meningococcal disease, to yield an attack rate of It may therefore be concluded that not all susceptible individuals develop invasive infection despite being colonized with an invasive isolate.

Studies performed more recently in the United Kingdom evaluated the correlation between bactericidal titers and disease incidence determined using laboratory surveillance data in various age groups for serogroup C and serogroup B For serogroup B, the highest incidence of disease was seen in infants 6 to 11 months of age, as presumably maternally derived antibodies decreased.

However, despite the decreasing incidence of disease through childhood, there was no apparent increase in the proportion of children with putatively protective bactericidal titers. These data contrast with the data of Goldschneider et al. Trotter et al. The simplest explanation is probably because of lower rates of carriage and exposure, but this alone cannot explain the high disease rates in infants. The role of opsonophagocytosis in conferring protection against meningococcal disease in the absence of serum bactericidal activity has received little attention.

The role of complement-dependent phagocytosis and complement-dependent bactericidal activity was studied with 62 strains of N. Strains that belonged to serogroups B and 29E, but not serogroup A, C, W, and Y strains, were killed by neutrophils following incubation with C8-depleted pooled human serum. While similar amounts of C3 were deposited on group B and group Y strains, only the former were resistant to direct complement-dependent killing.

Further, there was no correlation between opsonophagocytic killing and complement-dependent bactericidal activity among the group B and Y strains. In contrast to the C8-depleted pooled human serum, serum from an immunized C8-deficient patient could mediate opsonophagocytic killing, which suggested that opsonophagocytosis assumes a critical role in protection against meningococcal disease in persons deficient in components of the terminal complement pathway C5 through C9.

In particular, the efficacy of a meningococcal vaccine in such individuals would depend on opsonophagocytic activity. The reader is referred to reference for an in-depth review of these receptors. In vitro studies demonstrated that IgG1-mediated phagocytosis of S. The authors also examined 15 properdin-deficient individuals from 5 families, 7 of whom experienced one episode each of meningococcal disease and 8 who never had meningococcal disease. The risk of contracting meningococcal disease was 3.

Evidence for opsonophagocytic protection provides the rationale for immunization of terminal-complement-deficient patients against meningococcal disease. Antibody titers against group A and C polysaccharide were similar in 8 late-complement-deficient persons, 11 of their family members, and 7 unrelated normal individuals The decline in antibody responses was more rapid in complement-deficient persons.

However, the elicited anticapsular antibodies promoted opsonophagocytic killing. Enhancement in opsonophagocytic activity was similarly reported in three C7-deficient siblings following administration of the quadrivalent polysaccharide vaccine Eighteen patients with late complement defects who were given the quadrivalent polysaccharide vaccine were followed for 2 years.

Two episodes of meningococcal disease occurred in two patients at 9 and 12 months following administration of the vaccine One of the patients was presumed to have group C disease based on the observation of a significant increase in anti-group C polysaccharide antibody titers. This patient had relatively low levels of anti-group C antibody 4 months preceding the infection, which could have accounted for the susceptibility to invasive disease.

The serogroup that caused disease in the second patient was not known, and thus it is not clear why this individual contracted disease. Fijen et al. All patients generated functional antibody responses to immunization that were comparable to that seen in normal individuals. The majority of patients were followed for 6 years postimmunization; six episodes of meningococcal disease occurred.

Four of these were caused by group B strains that were not covered by the vaccine. The remaining two were caused by group Y. These latter infections both occurred in C8-deficient individuals, at 3. Antibody titers following administration of the polysaccharide unconjugated vaccine declines rapidly after 2 to 3 years, and therefore the occurrence of disease after this period does not necessarily constitute vaccine failure.

Revaccination of two C3-deficient and 17 late-complement-deficient patients resulted in robust increases in antibody titers Platonov and colleagues studied the efficacy of the quadrivalent polysaccharide vaccine in Russian patients with late complement component deficiency who experienced between one and five meningococcal infections Of 45 such patients, 31 were immunized with a quadrivalent meningococcal polysaccharide vaccine and were followed for 3 to 8 years.

As reported in prior studies, there was a good IgG response at 1 month after vaccination, which remained elevated for about 3 years. Revaccination of these terminal-complement-deficient patients 3 years after the first dose restored the total Ig concentrations to those observed 1 year after the first dose.

Six new episodes of meningococcal infection in four patients developed in the vaccine group. Among the 14 unimmunized patients, six episodes in six patients developed during the same study period. A significant survival benefit was detected, substantiating the need to vaccinate complement-deficient persons against meningococcal disease. Studies to determine the efficacy of the newer conjugate vaccines in complement-deficient patients will need to be carried out to document their efficacy in this population, although there is no reason to suspect that they will be less efficacious than the polysaccharide vaccine.

The use of quantitative PCR has enabled accurate quantification of bacterial loads in the bloodstream of patients with meningococcemia. A study of DNA levels in blood by real-time PCR in 1, patients throughout England and Wales showed that higher bacterial loads correlated with poorer outcomes The median bacterial load in 95 patients who died was 5. Higher bacterial loads were associated with prolonged hospitalization; digit, limb, or soft tissue loss; and the need for hemodialysis.

This study corroborated results from a previous study which also showed a correlation between higher bacterial load and severe disease median of 8. Bacterial load did not correlate with the duration of symptoms prior to admission.

It is not clear whether endotoxin released from bacteria results in complement activation or whether complement activation on the bacterial surface results in endotoxin release. The latter scenario may serve to explain why persons with terminal complement deficiencies have a more favorable outcome, and this is discussed below. The importance of lipid A structure in inciting inflammation was demonstrated in a recent study by Fransen et al.

Analysis of the LPSs of these strains revealed a penta-acylated lipid A because of mutations in the lpxL1 gene. Patients infected with lpxL1 mutant strains presented significantly less frequently with rash and had higher platelet counts, consistent with reduced cytokine induction and less activation of tissue factor-mediated coagulopathy. These data pointed to an important role for N.

The features of meningococcal disease in terminal-complement-deficient persons were characterized previously by Figueroa and Densen and have been confirmed in subsequent studies. Terminal complement deficiency is associated with a 7, to 10,fold-higher risk of developing meningococcal disease In some instances, relapses, defined as infection with the same serogroup recurring within 1 month of the prior infection, have been documented.

A plot of the logarithm of the number of infections sustained by each terminal-complement-deficient patient against the number of episodes of infection yielded a straight line The data supported the hypothesis that prior meningococcal disease does not protect these individuals from subsequent episodes of meningococcal disease. The risk of each episode of meningococcal disease was independent of prior episodes and was calculated to be It is not clear why prior infections do not protect this population from recurrent episodes, especially in light of data that demonstrate adequate antibody responses following natural infection , These antibodies are capable of supporting bactericidal activity in combination with normal human complement.

Immunization of these individuals with the polysaccharide vaccine also elicits an adequate antibody response that confers protection against disease Infection is likely to result in strain- and serogroup-specific immunity, while vaccination with the quadrivalent vaccine would elicit protective antibodies against four of the five major serogroups.

A possible explanation for this seemingly counterintuitive observation is that normal individuals develop durable natural immunity with age, while complement-deficient individuals always remain at risk for disease. Further, exposure to meningococcal strains may also increase during the teenage years. An increased risk of meningococcal disease caused by serogroup W and Y strains and other rare serogroups has been reported for complement-deficient patients , , , , A study of South African patients showed a significant association between rare serogroups and complement deficiencies.

There was a strong association between electrophoretic type ET , cluster F strains, and complement deficiency In contrast, serotyping, serosubtyping, and multilocus enzyme electrophoretic typing of meningococci showed no difference between isolates from 44 complement-deficient persons and from 50 complement-sufficient persons in the Netherlands with meningococcal disease The archives of the Netherlands Reference Laboratory for Bacterial Meningitis have data on all blood and CSF meningococcal isolates and have provided invaluable insights into the epidemiological aspects of meningococcal disease.

A total of 7, cases of meningococcal disease were reported between and Because of a doubling of the incidence of group B disease between and , 55 additional group B cases were included in the analysis. Of the selected cases, were available for further study and constituted the first study group.

The second group comprised 91 of the patients with disease caused by uncommon serogroups non-A, -B, or -C. None of the selected group B cases were associated with complement deficiency. Of the 32 patients with uncommon serogroups and complement deficiency, only 1 was under 5 years of age, highlighting the observation that complement-deficient persons are older than normal persons at the time of infection.

Properdin deficiency was detected in 13, C3 deficiency syndromes were detected in 6 3 with C3 NeF, 1 with factor H deficiency, and 2 with congenital C3 deficiency , and late complement deficiency was seen in In this study, persons with properdin or late complement component deficiencies had a slightly higher incidence of septic shock than the general population.

The severity of recurrent episodes was similar among the late-component-deficient individuals. However, the epidemiology of meningococcal disease has changed over the past 2 decades. Serogroup Y disease, which was relatively uncommon and still remains uncommon in Europe , is responsible for a third of cases in the United States. An epidemic of W disease that began during the Hajj in has spread to several countries. An epidemic caused by serogroup X has been reported in Niger.

It would be highly unlikely that a large fraction of cases caused by these strains are in complement-deficient persons. A more likely explanation is that these W, X, and Y strains are more virulent than previously isolated strains from these serogroups. Considerable genetic exchange occurs among meningococci, and modern molecular typing methods have divided meningococci into clonal complexes. Although the majority of strains within a particular lineage belong to a single serogroup, each lineage comprises strains that belong to more than one serogroup.

Whether the strains that cause disease in complement-deficient persons belong to less virulent lineages is not known. It is interesting that meningococcal strains that cause invasive disease in complement-deficient persons are all serum resistant Similar strains that cause disease in normal individuals are responsible for infections in complement-deficient persons With a few exceptions 88 , most strains that cause disseminated gonococcal infection DGI in complement-deficient individuals are also resistant to killing by serum from normal humans

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