LARGE PDF TEST
This PDF is intended as a companion to the podcast series, originally transmitted on So . the cat hits the mouse with a big CLANG . Try both and test it out. agencies, testing laboratories, consumer associations and academia bodies from countries large and small, industrialized, developing and in. Update: if you want really large (and valid!), non-optimized PDFs, use this command: pdftk $(for i in $(seq 1 ); do echo -n "resourceone.info "; done) cat output.
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Page Linked Adobe Page No. is a big part of what brought me to Mozilla a few years how we test, how we measure ability and .. can find all the books as HTML PDFs. Most platforms have a printer driver that can create pdf files, I would use this as a source rather than random pdfs from the internet. PDFs can.
This tool gives you more granular control over what level of optimization you want for the various components of your PDF. You can control image resolution, compression level, fonts to unembed, Acrobat version 6 or above gives you the ability to compress the entire file , and more.
Unfortunately, PDF optimization actually made the file over 2 times as large 16,K. This is a crude form of "refrying" your PDF that can be done with more precision with Distiller and a Postscript file see Optimizing PDF Files for more details on this advanced technique.
This option shrunk our PDF down to K, a savings of This still doesn't get us down to our self-imposed 5MB file size limit.
Time to go for plan B.
PDF IFilters Are Essential for Large PDF Environments
The easiest way is to simply print ranges of pages in your PDF. In our case we split the file up into two 65 page documents see Figure 7. Many of them have lower file size limits that prevent larger PDF files from being split. In the cortical bone of the lateral face Fig. It shows an almost constant thickness of about 1. A demarcation of the bulge in the cranial direction is difficult to make, as it gradually becomes thinner. In some cases, the medial and lateral cortical plate fuse with one another, forming one unified cortical plate Fig.
In other cases, the two plates run parallel to each other, separated by a thin layer of cancellous bone Fig. This demarcates the area where the drill holes can be optimally placed and constitutes the relevant experimental space available for the placement of the drill hole and the test substances green area in Fig.
This experimental space shows little variation in its height in the proximodistal direction Fig. The minimum necessary distance of the drill hole to the caudal margin Fig. On average this minimal necessary distance from the caudal margin was 3. The absolute largest value was 5.
The cortical region of interest inside of the defect is surrounded by a green frame while the medullary region of interest is depicted in blue.
The margins of the drill hole are presented as a black dashed line.
Newly formed bone is red and bone substitute materials yellow. Discontinuities in the cortical region left deep depressions that penetrated into the marrow space Figs. The bone tissue that filled the drill holes was a mixture of lamellar bone in the form of secondary osteons and interspersed remnants of plexiform bone Fig. Plexiform bone, which consists of woven bone and parallel fibered bone Fig. It initially fills the gaps and stabilizes the defect.
After mechanical stability is achieved, this primary bone is resorbed by osteoclasts and replaced by more mature secondary lamellar bone, formed by osteoblasts. In most cases, more than half of the primary plexiform bone in the cortical region had already been replaced by secondary osteons.
This process of remodeling was still going on at a very high rate, as proven by the presence of many large secondary osteons in all active stages of formation Fig. In the cancellous region of the defect, trabecular bone filled the space and was also a mixture of primary plexiform and secondary lamellar bone, but remodeling activity was far lower than in the cortex. Only a few hemiosteonal remodeling sites could be observed on the surface of the trabeculae.
In the autochthonous bone surrounding the drill hole, pre-existing trabeculae were compacted and thickened by layers of bone that had been added posttraumatically. A similar effect was seen at the periosteal surface surrounding the defects, where often large quantities of bone tissue had been laid down. More, but not all, of the primary bone had been converted by remodeling into secondary osteons. The most striking difference was the lower rate of ongoing remodeling.
These qualitative histologic findings were not significantly different between drill holes filled with autologous bone and those left completely empty. Bone regeneration was only about half as strong as in the cortical environment.
There were no significant differences between the two treatment groups. The drill hole in the empty control group was filled to The situation in the medullary space was not as unambiguous.
Again, there were no significant differences between the treatment groups. To characterize the completeness of bone regeneration in a cortical defect, it is important to measure the fraction of the area that was not filled with bone, but with soft tissues that invaded from the periosteal region and impaired bone formation. The percentage of these soft tissues in areas were only cortical bone should be was Variation was conspicuously high.
They are presented here more extensively in order to illustrate the quantitative healing properties of the experimental model. Description of technical problems with the model The exact placement of the drill holes proved to be the most severe problem.
The planned ideal defect, which should cut through the lateral cortical wall and then penetrate the medullary space with bone marrow surrounding it on all sides Fig. In some cases the drilling was placed too close to the caudal margin and the caudal cortical bone was penetrated leading to stronger bone formation due to the greater regenerative potential of this cortical region see histomorphometric results.
A drill hole placed too far caudally was subjected to disproportionately high bone formation Fig. If the drill hole is located too far cranially, there is a risk of cutting through the entire bone thickness, which is thinner in these regions Fig.
The titanium pins marking the centre of the defects proved to be unnecessary. Even after long observation periods, the empty drill holes were clearly visible on x-rays. Degradation of bone graft substitute material was easily followed over periods up to one year. A critical size model could not be established. To uphold and improve standardization, surgery should be restricted to the middle part of the caudal margin because of the regional differences in the height and width of the bulge mentioned above.
The narrower the chosen region is, the more similar the anatomical and histological characteristics will be. These measurements apply to the adult female Land Merino breed and will differ in other breeds and in male sheep. Precision operating technique is needed in this model and is perhaps the most challenging aspect with the greatest influence on standardization.
That a true critical size defect is not possible in this anatomical site is, indeed, an admitted weakness. The immediate milieu and environment of drill hole test sites consists of well vascularized muscle tissue on one side and bone marrow on the other side providing a plethora of progenitor cells and factors necessary for defect healing.
Because of this, the region facilitates substantial new bone growth and, in longer observation periods, allows the evaluation of remodeling and degradation of bone substitutes. Sheep are compliant and docile animals [ 23 ] and are a less controversial test subject in the public opinion than, for example, the dog.
The body weight of sheep and the size of its long bones are roughly similar to those of humans. Their remodeling rate, lamellar bone structure and primary bone healing characteristics are similar to humans [ 11 ].
Monitoring and delivery techniques can be the same as those used in humans. When biomechanical testing is important, large animals such as the sheep have an advantage over rodent models [ 24 ] as they more readily approximate human anatomy. A number of models have been developed, also in the sheep and also utilizing drill hole defects, to test bone graft substitutes [ 12 , 23 — 25 ], some placing the drill holes in the long bones of the extremities, others using a combination of femur drill holes and a slot defect in the tibia [ 26 — 28 ].
The comparison of different variants or different dosages of bioactive substances is best achieved when comparisons of all can be made in a single animal. Nuss et al. Van der Pol achieved a higher degree of standardization [ 29 ] by using customized drilling jigs but in sites in two different bones the tibia and femur. Gisep et al. The use of different anatomical bone sites are not, however, comparable with regards to loading boundaries and amount and quality of new bone growth and bone densities [ 24 ].
The site of a bone defect has a large influence on its properties of regeneration. The density of bone in various anatomic sites varies widely [ 24 ]. When multiple defects are drilled in the epiphysis, their differing proximity to the metaphysis can directly influence growth and tissue characteristics.
Defects placed in the metaphysis and the neighboring diaphysis differ starkly in new bone growth [ 30 ]. Bone regeneration is site specific; in our model, all graft samples and controls are placed in the same osteologically homogenous anatomical region. Different bone sites are also influenced by the type of tissue in its immediate vicinity i.
The use of bilateral defects, in which limbs on both sides of the animal are affected, are discouraged due to animal welfare reasons [ 7 ]. A model in which all test substances can be implanted in a single animal can keep animal numbers down [ 31 ].
The assessment of multiple defects in one animal provides for control of variation between animals and thus limits the number of animals needed [ 7 ]. Indeed, the main advantage of this model is the possibility of implanting 5 different test items or allowing 5 treatment groups in a single large animal while refraining from setting a bilateral defect.
This model allows for implantation biocompatibility testing of new bone graft substitutes as well as efficacy testing, although short term evaluations maybe more efficient in, or in combination with, a rodent model. Short term observation periods would allow for the tracking of inflammatory reactions, osteofibrosis or osteonecrosis. The model lends itself particularly well to following and comparing the degradation characteristics of bone graft substitutes and their replacement with new bone over longer periods of time.
Clearly, no animal model matches human physiology perfectly. Sheep do tend to have higher trabecular bone densities than humans, depending on site [ 32 , 33 ].
Although some breeds cycle all year round, sheep are seasonal breeders that have varying oestrogen levels over the course of the year and this must be taken into account during the study design phase and season of the year of any interventions reported [ 18 , 34 ].
This model also allows for the use of autologous graft that is comparable to the cancellous graft applied in clinical human use — something that is not possible in rodents in which typically only bone marrow with cortical bone and periosteum is available for grafting and in which osteogenic colony forming units in grafts are much lower than in humans [ 7 ]. Aside from the practicalities and the mechanical factors that speak for the use of large animals in bone regenerative medicine, there are other biological reasons as well.
An example of this is the difference in bone regeneration between small animals and large animals as can be seen in the fact that calcium phosphate scaffolds rarely show osteoinduction in rodent models while successfully inducing bone growth in large animals [ 35 ].Now, simply print the sample PDF file, and you shall have your own customized lined paper.
This still doesn't get us down to our self-imposed 5MB file size limit. Standardization may be the key to moving systematically towards better bone regeneration. Unicorn Meta Zoo 2: Defects placed in the metaphysis and the neighboring diaphysis differ starkly in new bone growth [ 30 ]. Surgery The animal was laid in lateral recumbency. All soft tissue was separated from the bone with a periosteal elevator.
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