TABLE 3

The standard 4-trocar technique was applied for LC maintaining pneumoperitoneum at a pressure of 14 mmHg with some modifications [1]: Application of a 5th port in some cases for elevation of the hypertrophied left lateral liver segment [2], The subxiphoid port was placed more to the right of the midline, while the umbilical port was put on the right, left of the midline or below the umbilicus by open Hasson technique to avoid injury to the falciform ligament recanalized umbilical vein [3].Abdominal wall collaterals were assessed pre-operatively by abdominal CT; moreover, trans-illumination of the abdominal wall during port placement was done to identify these collaterals preventing catastrophic bleeding [4], Avoiding excessive traction to prevent avulsion of gallbladder from its bed, aspiration of gallbladder content (empyema or mucocele) to facilitate its grasping, and avoiding blunt dissection Fig. 1 [5] careful dissection by using either Harmonic device (Ethicon Endo-Surgery, Cincinnati, OH) in some cases (its use was according to its availability or intra-operative findings (i.e. numerous collaterals and/or marked adhesions)), Fig. 3, Fig. 4A or monopolar electrocautery in other cases, Fig. 4B moreover, good hemostasis of gallbladder bed was done by using Argon device, Fig. 5Aoxidized cellulose (Gelfoam) (Pfizer, New York, NY), surgicel (Johnson & Johnson, New Brunswick, NJ) Fig. 5B and/or radiofrequency ablation (Habeeb sealer), furthermore, preparation of sufficient amount of FFP, platelets, and packed red blood cells (PRBCs) was done to be used when needed.

Optimal criteria to define COPD-related airflow obstruction

The definition of obstruction remains a highly controversial issue. Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines continue to define airflow limitation by a fixed FEV₁/forced vital capacity (FVC) threshold of 0.7, independently of age and sex. This is in marked contradiction with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines, which clearly recommend that the lower limit of normal (LLN) criterion is used. Several large series in which investigators assessed lung function in adults challenge the GOLD guidelines. The first study [27], performed in 14,506 adults, found that the fixed ratio (as compared to the 1993 European Community for Steel and Coal (ECSC) study [28]) has a high negative but a low positive predictive value, particularly in patients aged >50 yrs (fig. 1⇓): the false positive rate was 33% in the 61–70 yr age range. Similarly, in the NHANES-III (Third National Health and Nutrition Examination Survey) population, the proportion of older adults misclassified by the fixed ratio was nearly one-fifth, whereas nearly one-half of young adults were false-negative with GOLD guidelines, in comparison with the fifth percentile criteria [29]. A third study compared the GOLD and British Thoracic Society (BTS) guidelines (FEV₁/FVC <0.7 for both, BTS requiring also a FEV₁ <80% predicted) to published equations (including ECSC/ERS) and their corresponding LLN [30]. The prevalence of airway obstruction according to these criteria was evaluated in the NHANES survey, a health survey in England (UK) and a longitudinal study in Dutch population. With most prediction equations, the LLN was <0.7 at a mean age of 42 yrs in males and 48 yrs for females. The prevalence of obstruction with the 0.7 criterion reached 45% in healthy subjects aged 60 yrs or more. Using LLN derived from prediction equations lowered the prevalence to between 12.3% and 15.5% in healthy lifelong nonsmokers. Underestimation of airflow obstruction in younger patients with the GOLD criteria was confirmed in a longitudinal study [31]. Among adults aged 20–44 yrs included in the European Community Respiratory Health Survey (1991–1993) and re-evaluated in 1999–2002, the LLN criteria detected 5.1% of patients with airflow obstruction, among whom only 45.6% were below the 0.7 cut-off. Subjects with airflow obstruction that were missed by the fixed ratio were younger and 64% were females. During follow-up, the proportion of subjects exhibiting a FEV₁ <80% pred, chronic cough or phlegm, or being treated for respiratory problems was significantly higher in misidentified subjects than in those without airflow obstruction by both criteria.

New diagnostic techniques

High-resolution computed tomography (HRCT)Other Section

X-ray computed tomography (CT) has been in commercial use since 1972 (3), and has been revolutionary in providing insight into pulmonary structure and function in vivo. The technology involves an X-ray beam source with a row of detectors positioned opposite—the source and detectors are assembled in a circular arrangement that rotates around the patient through 180 degrees. Measuring the attenuation of narrow X-ray beams as they pass through tissues of varying densities allows the construction of a 2-dimensional (x,y) axial ‘slice’ through the body. The digitised image slices are comprised of pixels with relative ‘densities’ [measured in Hounsfield Units (HU)] that are representative of the tissue density in that location. Early scanners used relatively thick, contiguous slices that were obtained along the cranio-caudal (z) axis as the patient was moved stepwise through the scanner.

High-resolution CT achieves its increased spatial resolution by the use of thinner detectors, which allows the effective thickness of the axial slices to be reduced, usually to around 1 mm. The physical size of the X-ray detectors is therefore one of the determinants of resolution, while scanning technique is the other and more dominant determinant of spatial resolution. The high-resolution technique traditionally involves axial or 2-dimensional scanning, i.e., subjects are stationary during a single tube rotation to acquire a single cross-sectional slice. Because of the increased time and radiation required to perform contiguous thin slices, the slices are typically separated along the z axis by an interval of around 10 mm, which minimises total radiation exposure but images only 10 percent of the lung. It is therefore suitable for imaging the lung parenchyma but not for detecting, for example, mass lesions.

These days, almost all CT scans are performed in ‘helical’ or ‘spiral’ mode, rather than the older axial technique. That is, the patient is moved continuously through the scanner during tube rotation, effectively producing a ‘cork-screw’ motion. In this way, 3-dimensional or volumetric data is obtained; the faster the patient is moved through the rotating tube (pitch), the faster the acquisition time and the lower the radiation exposure. However, this effectively produces greater blurring of the images and reduces spatial resolution. Hence imaging technique, including tube current and voltage, once again has a large effect on spatial resolution.

Post-processing of the raw image data produces reconstructions in three orthogonal planes, which are most commonly displayed as axial images. Reconstruction also involves algorithms to produce images that are optimised for diagnostic viewing, such as ‘high-resolution reconstruction algorithms’. These produce sharper but noisier images. Advances in CT technology have led to faster tube rotation, greater detector sensitivity and more rows of detectors – now up to 128 rows. This has greatly reduced acquisition time and reduced breath artifact; computer algorithms are able to correct for artifacts related to image inconsistency and motion (4). Axial slices of any thickness can be reconstructed, down to around 0.5 mm thickness (see Figure 1). However, at this level, spatial resolution is determined more by scanning technique (e.g., table speed) than by reconstructed slice thickness. There may therefore be no major advantage in such thin reconstructions. Modern post-processing techniques also allow true 3-dimensional reconstruction of the entire lung, airways and vasculature. Whether these are clinically useful is arguable.

Figure 1 High-resolution CT scan of a 69-year-old man with allergic bronchopulmonary aspergillosis. Three axial reconstructions of (A) 6 mm, (B) 2.0 mm and (C) 0.625 mm thickness. Note the increasing spatial resolution with decreasing slice thickness. (Helical acquisition with the following settings to maximize spatial resolution: 120 kVp, 548 mAs, tube rotation time 0.5 s, collimator width 0.625 mm, pitch 1.375, voxel dimensions 0.76 mm × 0.76 mm × 0.625 mm).

Assessment of emphysema

HRCT is ideal for the detection and characterisation of emphysema (5). Moreover, it is very straightforward to use HRCT images to quantify the extent of emphysema. Older, standardised visual scoring systems to quantify emphysema (6) were subject to a high degree of inter- and intra-rater variability (7). More recent computer-automated quantification tools have removed the subjectivity of scoring (7). Emphysematous lung is represented by image voxels (the unit of a 3-dimensional image dataset) of density less than around –900 HU, which equates to a density of around 0.1 g/mL (water has a density of 1 g/mL). Identification of all voxels of density less than this threshold is a process commonly known as ‘density masking’, and the volume of the emphysematous lung can be calculated by multiplying the voxel numbers by the known volume of the voxels (8). A commonly used index is the percentage of low-attenuation areas (LAA%), which expresses the emphysema volume as a proportion of total lung volume measured by CT. The LAA% has been shown to correlate with FEV₁ (9-11), diffusing capacity for carbon monoxide (DLCO) (9), the frequency of COPD exacerbations (12), BODE index and quality of life scores (13). These relationships confirm that the severity of emphysema is a determinant of the severity of airflow limitation as well as the clinical expression of disease.

A proposed clinical application of quantitative CT is in the longitudinal monitoring of emphysema progression. In the ECLIPSE study, which was a 3-year prospective, multi-centre observational study of COPD patients, emphysema progressed and became more extensive over the study period (14). The observations also confirmed that the extent of emphysema predicted the rate of decline of FEV₁ (15). Although it may be useful in identifying the so-called ‘emphysematous phenotype’, the ECLIPSE study also re-emphasised the marked clinical heterogeneity among COPD patients (16). More work is therefore needed to determine precisely how changes in CT emphysema over time translate into clinically important outcomes.

The LAA% gives an estimate of emphysema quantity, but not its distribution. The importance of emphysema distribution was demonstrated in the NETT (National Emphysema Treatment Trial) study of patients undergoing lung volume reduction surgery (LVRS). In this study, patients who had predominantly upper lobe emphysema (i.e., localised or heterogeneous emphysema, so-named because of the obvious differences in emphysematous and relatively preserved regions in the same lung) had improved survival following LVRS compared to the control group. In contrast, those in whom emphysema was not localised but rather spread out over a large proportion of the lung had poorer clinical outcomes (17).

In addition to this spatial heterogeneity, emphysematous lesions also exhibit so-called ‘fractal geometry’. This is measured by identifying emphysematous clusters, i.e., a discreet and isolated zone of emphysema. In COPD, there is a large number of small emphysematous lesions but only a small number of large lesions or cysts. Plotting a cumulative frequency of emphysematous lesion size in log-log space results in a linear relationship with a negative slope (18). The slope of that relationship is the ‘fractal dimension’, with a more negative slope indicating a more heterogeneous distribution of emphysema zone sizes. As an example of its clinical significance, Coxson et al. (19) showed that the fractal dimension derived from the pre-operative CT predicted the change in exercise capacity following LVRS. Although this complex CT assessment of emphysema appears to have some clinical significance, its potential role in routine clinical practice remains unclear.

Assessment of airways

Airways are also visible in HRCT image data, down to approximately generation 6 or 7. In COPD, changes in small airways (terminal and respiratory bronchioles) are considered to be the among the earliest signs of disease (20) and precede the development of emphysema (21). However, CT airway measurement is much more difficult than measurement of emphysema for a number of reasons. Firstly, airway branching is asymmetrical (in terms of length and calibre of bronchi) and hence ‘functional’ classification of individual airways cannot be made by simple counting of generations (22). Indeed, the small airways (0-2 mm in diameter) can be found anywhere between the 4^th and 14^th generations (22). Secondly, the measurable parameters of airway geometry (such as airway wall thickness and luminal area) vary greatly by anatomical location (23). Finally, since the major site of airflow obstruction in COPD is in airways with dimensions less than 2 mm (20,21), the primary area of pathology is generally below the resolution of conventional HRCT.

Early attempts at quantitative analysis of visualised (generally large to medium sized) airways involved manual tracing of internal luminal area (Ai), outer area (Ao) and the calculation of wall area (Aw). Computer algorithms using a density mask have been used to automate this process, whereby circles surrounding the airway lumen are progressively ‘eroded’ based on density measures until the airway wall and lumen are identified (24). Another method known as the full-width-half-maximum method has been used to identify internal and external wall edges. This principle uses density analysis along radial ‘spokes’ from the centroid of the lumen, and identifies the wall edge as the point where density is half way between the local minimum and local maximum along each spoke (10). A well-documented problem is that CT measurement systematically over-estimates Aw and underestimates Ai, a feature that alters with airway angle and becomes more pronounced with decreasing airway calibre (24); mathematical corrections can be applied to overcome this error. Automated airway measurements have been validated for larger airways (down to the 6^th generation) (25,26), but concerns regarding accuracy continue to limit their use.

Measurement of the small airways is even more problematic. Although large airway wall thickness correlates with symptoms (27) and lung function (10,25) in COPD, and may be predictive of small airway abnormalities (28), direct measurement of small airway geometry by CT has remained elusive. ‘Air trapping’ is an indirect HRCT measurement of small airway dysfunction, where lung lobules remain inflated due to airway obstruction and hence show a less-than-normal increase in attenuation during expiration, creating a mosaic pattern of attenuation. However, this phenomenon is observed to a degree even in healthy, non-smoking individuals without airflow obstruction (29,30). In COPD, this method is further complicated by the presence of emphysema, which itself shows low-attenuation during expiration (31). Although attempts at quantifying air trapping in the presence of COPD have been made (31,32), more validation studies are needed to determine the best method. For now, at least in the clinical setting, it seems that air trapping on CT will remain a more qualitative marker of small airways disease, and probably adds little to the diagnosis or monitoring in COPD.

Ventilation CT

Although anatomical information from CT is of value for diagnosis and assessment of disease severity, there is likely added benefit when it is combined with imaging-derived measurement of lung function. For example, the distribution of inhaled xenon (Xe) gas (which is radiopaque, and distributes into the airways and alveoli on inhalation) can be measured by its CT attenuation. The CT density of these Xe-containing airspaces increases linearly with Xe concentration (33). In this way, specific ventilation (i.e., ventilation per unit lung volume) can be measured and the regional distribution of ventilation explored. New dual-energy (i.e., two X-ray sources) CT allows both dynamic and static evaluation of regional ventilation, and simultaneous acquisition of anatomical and ventilation images (34). This eliminates the problems of serial scanning, such as differences in breath-hold volume affecting density, and spatial misregistration of the two scans (35). Dual-energy Xe gas ventilation scanning has been shown to reliably quantify both emphysema and airways disease (36).

Limitations of CT

In addition to problems with spatial resolution, CT has other important limitations. For example, there are minimal data regarding normal ranges for airway dimensions (37) and currently no consensus standards for validation and quality control of CT airway measurement—a prerequisite for high-quality, longitudinal studies. Perhaps the most important limitation of CT is the risk posed by ionising radiation, particularly with serial scanning (38). Quantitative measurements using current-generation detectors with low-dose protocols may be acceptable for certain applications (39) but the reduced signal-to-noise ratio poses an additional challenge when assessing small airways (40,41).

Ultra-high-resolution imagingOther Section

Like all diagnostic tools, imaging techniques need to be verified against a gold standard test. In the case of COPD, this would be histopathological evaluation of lung tissue. However, even as a gold standard, histopathology itself has problems: tissue changes from fixation, cutting and drying as the specimen is processed cause measurement error; the small size of specimens may introduce sampling error; and analysis is generally performed in two (or even single) dimensions, giving only estimates of the 3-dimensional structure (42). The use of ultra-high-resolution imaging techniques is aimed at countering these problems.

Micro-computed tomography (micro-CT)

Micro-CT is similar to conventional CT in that it uses an X-ray source and detectors that are arranged around the study object. Like conventional CT, full volumetric data is captured. However, the source and detectors are brought much closer to the specimen, and the specimen itself is rotated while the X-ray source and detectors stay stationary. This allows exceptionally higher resolution (down to 1 µm per voxel), which is ideal for studying the lung microstructure including that of the small airways. The trade-offs are that only small specimens, i.e., excised tissue or small animals, can be imaged. Furthermore, the samples are exposed to high radiation doses that are damaging to living tissue.

Micro-CT was first used to image lung parenchyma by Watz et al. (43), who used a hot formalin vapour fixation technique and silver nitrate staining to provide the necessary contrast. This provided spectacular images of alveoli and terminal airways, and even allowed a “virtual bronchoscopy” through an alveolar duct (43). The technique has subsequently been validated against light microscopy in mouse lungs (44). It has also been used to generate gold-standard airway measurements from explanted lung to calibrate 3-dimensional airway measurements made by whole body HRCT (45). Figure 2 demonstrates the spectacular detail obtained using micro-CT of the lung. In COPD, micro-CT has been used to demonstrate the loss of terminal bronchioles in early-stage disease, which has been suggested to precede the microscopic emphysematous destruction of the alveoli (21).

Figure 2 Micro-computed tomography (micro-CT) of a 2 cm pig lung cube. Lungs were inflation-fixed in formalin steam prior to scanning. (A) Cross-sectional high-resolution CT image and (B) corresponding micro-CT image of the same region of interest. Exquisite detail is seen with micro-CT. Scale bars =1 cm.

Although living, in vivo human studies are precluded (due to both specimen size and the radiation dose), micro-CT has provided fascinating insights into the structural changes in COPD. The technology, in its currently form, will likely remain limited to research. It may play a future role in, for example, developing disease-modifying therapies in animal models.

Synchrotron imaging

This form of imaging utilises the properties of particle beams, e.g., electrons, in a particle accelerator. The particles are in continuous motion at near the speed of light, held in line by electromagnetic fields. When the particles are accelerated further they emit X-rays with a wide energy range, allowing a wide range of samples to be imaged, and a high photon flux, which allows fast acquisition times. The result is an image with resolution in the 1-10 µm range (46), which is ideally suited to studying the microstructure of fine tissues such as the lung.

The technique has been used to define the structure of both mouse (47) and human (48) lung acini ex vivo, as well as in vivo whole mouse lungs (49). The high temporal resolution also makes functional imaging possible, including pulmonary acinar mechanics (50) and regional ventilation (51,52). In COPD mouse models, it has been used to identify early emphysematous changes (53,54). While the anatomical detail is impressive, synchrotron imaging is yet to provide significant functional information on human lungs, being hampered by the limitations of specimen size (necessitating excised tissue or small animals only), radiation damage to tissues, and the need for a particle accelerator.

Nuclear medicine imagingOther Section

Unlike CT imaging methods, which are based on the relative absorbance of radiation transmitted through the tissues from an external source, nuclear medicine techniques utilise tracers that emit radiation and are introduced into the organs. This has been used to image a variety of body tissues and organs, including bone, the heart and the brain. Nuclear medicine scanners are in routine clinical use for the diagnosis and staging of malignancy. They have also long been used for the diagnosis of pulmonary embolism (PE)—this involves intravenous injection of radioisotopes to the pulmonary vasculature and inhalation to the peripheral airspaces, thus giving functional images of ventilation and perfusion.

Positron emission tomography (PET)

PET is a 3-dimensional nuclear imaging technique, which utilises radioisotopes that emit positrons as they decay. A positron is a sub-atomic particle found in the nucleus, with the same molecular weight as an electron. As the positron makes its way out of the nucleus, it encounters a free electron—these two oppositely-charged particles combine and ‘annihilate’ each other. In the process, two identical beams of gamma-radiation are emitted at 180 degrees to each other—beams detected at or very near the same time are considered to be ‘coincident’ i.e., from the same source. The location of the source particle can therefore be determined geometrically from coincident beams, being located on a straight line between the two detectors. However, this localisation is affected by beam scatter, the presence of random coincidences, and by attenuation as the beams travel through tissues of different densities. Corrections for this image noise can be made during image processing, which includes the use of a tissue density map i.e., a CT scan. Many scanners incorporate multi-detector CT (PET-CT) so that, in addition to providing a tissue density map for attenuation correction, organ function can be superimposed onto the CT images. This image co-registration has an obvious application in oncology for localisation of active tumour cells for targeted treatment.

The most commonly used PET radioisotope is fluorine-18, which has a half-life of approximately 110 minutes. This isotope is attached to fluorodeoxyglucose (FDG, a glucose analogue) to form the radiotracer 18F-FDG. The radiotracer is taken up by metabolically active tissue—a property used to identify cancerous tissue in the lungs and surrounding structures. In COPD, 18F-FDG has been used to demonstrate an increase in neutrophilic inflammation in the lungs compared to controls and to those with alpha-1 antitrypsin deficiency-associated emphysema (55). This provides interesting insights into COPD pathophysiology and is a non-invasive, in vivo measurement. However, it is also potentially useful in studies of new therapies targeting neutrophils, given their role in the pathogenesis and pathophysiology of COPD (56).

Regional ventilation can also be measured by PET using the PET isotope nitrogen-13 (13NN) gas dissolved in saline. A peripheral venous injection of this tracer enters the lung via the pulmonary arterial circulation. Due to its low tissue solubility, the 13NN then rapidly diffuses across the alveolar membrane. An initial breath-hold during injection allows the 13NN to enter the lung in direct proportion to blood flow, which allows measurement of regional perfusion. Regional ventilation can subsequently be measured by the decrease in 13NN activity over time as the subject breathes, clearing the 13NN in direct proportion to ventilation (57). Combining this information thus produces the regional distribution of lung ventilation/perfusion ratios (V/Q). Quantification of regional V/Q by PET has been shown to correlate closely with global measures of gas exchange such as arterial partial pressure of oxygen (PaO₂) (58). Using this 13NN technique in COPD, Brudin and colleagues (59) reported that high V/Q tended to be more common in subjects with an emphysematous phenotype, whereas low V/Q was more common in those with a small airways disease phenotype. This is consistent with the archetypal concept of ‘pink puffers’ and ‘blue bloaters’.

While much of the focus in COPD is on airways disease and changes in regional ventilation, there has been an increasing focus on the role of the pulmonary vasculature in this disease. Vidal Melo et al. (60) found that regional heterogeneity in Q was increased in patients with mild COPD compared to healthy controls, in a manner that was independent of changes in regional tissue density. This very interesting finding suggests that regional changes in pulmonary blood flow, perhaps due to inflammation, may precede lung parenchymal changes in COPD. This may have utility as a biomarker for early disease.

One limitation of PET, with its short half-life radioisotopes, is the need for a cyclotron and radiopharmaceutical formulation often on-site. Additionally, for repeated studies, the radioisotope has to decay enough to avoid signal contamination. Adjustments following a ‘baseline’ scan prior to repeat administration help overcome this problem, however rapid, repeat testing is generally not possible. The spatial resolution of PET does not allow imaging of individual gas exchange units, although it is probably sufficient to separate physiologically meaningful differences in regional ventilation.

In spite of these limitations, and its relatively recent inception, PET may have a significant future in the study of COPD. The recent findings regarding regional distribution of blood flow may provide insight into the role of vascular remodeling, especially with regard to longitudinal changes and therapies targeted at this process.

Single-photon emission computed tomography (SPECT)

SPECT is similar to PET in that a radiotracer is introduced to the body, and the radiation it emits is detected externally. However there are several key differences. SPECT radioisotopes emit a single gamma-beam as they decay, as opposed to the two gamma beams emitted simultaneously from PET isotopes. This results in a lower radiation exposure to the patient, at the expense of an increased acquisition time per image. Increased scanning time may decrease resolution due to movement artifact, although there have been attempts to overcome this with breath hold/respiratory gating (61). The spatial resolution of SPECT is less than that of PET, however it is more widely available, and SPECT radiotracers are easier and cheaper to manufacture. SPECT has been a major advance in nuclear imaging for suspected PE (62), as opposed to the traditional planar lung scintigraphy. The more recent appearance of SPECT-CT fusion has helped overcome a lot of the resolution and anatomical registration problems, and can provide true 3D assessment of regional lung function (63,64).

In addition to its diagnostic role for PE, SPECT can give us insights into pulmonary physiology, both with respect to ventilation and perfusion. Perfusion scanning is generally performed using 99m-technecium labeled macro-aggregated albumin (^99mTc-MAA), which lodges in the pulmonary circulation after peripheral injection. Ventilation scanning requires inhalation of gaseous radioisotopes or radiolabeled particulate aerosols. A true gas distributes throughout the whole lung, and differences in its regional distribution reflect differences in regional ventilation. Dynamic SPECT could therefore potentially give information on the time course of ventilation in different lung regions. Both ^81mKr (65) and ¹³³Xe (66) have been used to demonstrate ventilation heterogeneity in COPD.

Unlike true gases, particulate aerosol tracers are ‘deposited’ in the lung and have the advantage that imaging can be performed without the tracer continuously redistributing. Also, aerosols will not distribute by collateral ventilation between lung units, which is increased in COPD compared with healthy lungs. However, aerosol particles of a diameter 0.5-1 µm are 1,000 times larger than gas molecules and are therefore transported by convective ventilation only (67). The distribution of radioaerosols therefore neglects diffusive ventilation, which is the predominant mode of gas transport within acini beyond the terminal bronchiole (68). In COPD, airway narrowing and emphysematous destruction likely brings the convection-diffusion front more centrally so that a larger volume of the lung ventilates by diffusion compared with healthy lungs. Therefore, the interpretation of inhaled radioaerosols distributions in COPD should take these physiological changes into account (69).

A commonly used aerosol tracer is 99m-technecium-labelled diethylene triamine pentaacetic acid (^99mTc-DTPA). The generated particle size is around 1 µm but this increases on entry into the airways due to agglomeration. These larger particles deposit onto large airways, particularly at airway branch points, causing ‘hot-spots’ on the ventilation image (70). Technegas is a ^99mTc-labelled, aerosolised ultra-fine carbon particle of approximately 200 nm diameter. It is used routinely in Australia (where it was invented) and other countries in V/Q scanning for the diagnosis of PE. Due to its small particle size, the distribution of Technegas approximates that of a true gas (71), even in the presence of severe airflow obstruction (72) (Figure 3). Technegas deposits more homogenously, and is less susceptible to central airway deposition or movement after inhalation, than ^99mTc-DTPA (73).

Magnetic resonance imaging (MRI)Other Section

MRI has the advantage of not requiring ionising radiation. Its usefulness for lung imaging has traditionally been limited by technical factors and, consequently, there has been much less MRI lung imaging in research and clinical practice compared with the modalities already discussed. The technique employs large magnetic fields, which alter the behavior of individual atoms. Conventional MRI utilises the nuclear spin properties of hydrogen atoms, found in abundance in water. In their natural state, hydrogen ions (or protons) spin on an axis in random orientations. The application of a strong and uniform magnetic field causes them to align parallel or anti-parallel to the field. When the magnetic field is switched off, the spinning protons return to their natural state and in the process release a burst of radiofrequency energy. It is this energy that is detected by the MRI scanner, and is used to construct the image. MRI has excellent anatomical resolution in tissues of high water content, such as the brain. However the lung, being mostly air, has a low density of hydrogen ions, meaning low signal intensity and poor signal-to-noise ratio. Conventional proton MRI images of the lung therefore have low contrast and contain little meaningful information. Additionally, being comprised of air-filled alveolar sacs, the lung has millions of air-tissue interfaces. Each of these causes decay of the radiofrequency signal as it travels through the lung, known as ‘susceptibility artifact’, which contributes to poor signal intensity (81). Such inherent limitations have left the lung relatively unexplored by MRI. However, the large potential for MRI imaging of the lung has been recognised for decades (82) and thus many attempts have been made to overcome these barriers.

Inhaled noble gas MRI

Inhaled noble gases have been used to overcome the aforementioned limitations (83). Unlike particulate aerosols, gases undergo ‘self-diffusion’ by random Brownian motion, where the gas molecules continually move further apart until stopped by a physical boundary. The speed and direction of movement is determined by the physical properties of the gas, and the likelihood of colliding with a neighbouring gas particle i.e., the local concentration of the gas. An example of a noble gas ventilation agent is hyperpolarised helium-3 which, unlike air, is highly excitable by a magnetic field and thus provides excellent MRI contrast. It diffuses freely in air at a rate of 0.88 cm²/s, which means that, over a timecourse of 2 ms, an individual molecule will travel 0.59 mm. Given that the typical acinar size is 0.3 mm, the diffusive movement of a molecule of ³He in an acinus will be limited by the alveolar boundaries within the 2 ms timeframe—that is, its diffusion will be ‘restricted’ from 0.88 to 0.2 cm²/s. The restricted gas molecule movement is measurable by MRI, and is known as the ‘apparent diffusion coefficient (ADC)’. A high ADC indicates that the alveolar walls are further apart, i.e., there is alveolar destruction or acinar expansion, which is an early sign of emphysema (84). The technique has been validated against histological specimens (2). It is increased in smokers who still have a normal FEV₁, suggest that alveolar expansion and early emphysema are present even without clinical manifestation of disease (85). The ADC also correlates very closely with standard lung function measures including FEV₁/FVC ratio, TLC and RV (85). In more advanced disease, the mean ADC correlates strongly with FEV₁ (86) and DLCO (87), in fact more strongly than HRCT measures of emphysema (86,87).

From a functional perspective, ventilation can also be assessed using the properties of inhaled noble gases. Inhalation of the hyperpolarised gas distributes reasonably homogeneously in healthy young adults, but is heterogeneous in otherwise healthy elderly subjects (81). Regions of absent MRI signal, which indicate non- or poorly-ventilated lung units, have been shown to correlate with emphysema that is detectable by CT or the ADC (88). Ventilation defects may also be observed even in the absence of anatomically gross emphysema visible by CT (89,90). In this case, small airways disease, mucous plugging or a combination of both small airways diseases and microscopic emphysema are possible explanations for absent ventilation. This suggests that, like PET and SPECT, functional disturbances measured by MRI may be more sensitive markers of early abnormalities in COPD, compared with anatomical imaging by HRCT.

The ability of hyperpolarised ¹²⁹Xe to diffuse across the alveolar membrane into the circulation allows gas exchange to be measured. There is a large chemical shift of ¹²⁹Xe between the gas compartment, the dissolved (tissue and plasma) compartment and the red blood cells (91). By detecting the change in resonance frequency between these compartments, measures of the alveolar membrane thickness (91) and blood uptake (92) can be made. This technique has been used to demonstrate the influence of posture on regional perfusion heterogeneity (93) as well as ventilation heterogeneity (94) in COPD.

Oxygen-enhanced MRI

Although the use of hyperpolarised noble gases has greatly advanced the use of MRI for lung imaging, these gases are expensive to use, requiring specialised laser polarising equipment and dedicated detectors. ³He in particular is in limited and restrictive supply. There is therefore a need for simpler and less expensive contrast agents. Oxygen was suggested as a MRI contrast agent by Edelman (95) over 15 years ago as a way of overcoming the inherent limitations of conventional proton MRI and avoiding the problems of hyperpolarised gases. Ohno and Hatabu (96) have written a detailed review of the theory and application of oxygen-enhanced MRI. In basic terms, molecular oxygen is weakly paramagnetic and, in the concentrations found in air and in blood, provides little MR signal. The inhalation of 100% oxygen produces a high concentration of oxygen in alveolar tissue and in blood, where is it predominantly dissolved in plasma. The result is an increase in the signal intensity, which then allows visualisation of the pulmonary parenchyma. The difference between room-air and oxygen-enhanced images represents ventilation to that area. Edelman’s original publication (95) clearly showed ventilation defects in a patient with emphysema. Ohno and colleagues (97) showed that oxygen-enhanced MRI was as good as CT at quantifying pulmonary emphysema across a wide range of severities, and correlated reasonably well with FEV₁ and DLCO. Recent work in subjects with COPD has shown increased heterogeneity of V/Q distribution measured by oxygen-enhanced MRI even in those without CT-defined emphysema (98), which varies with the severity of COPD (99).

The advantages of oxygen-enhanced MRI (OE-MRI) are that it is a simple, low-cost and safe alternative to hyperpolarised gas MRI. One of the limitations is that the gas itself is not directly visualised, but rather the tissue and blood, so that OE-MRI is only an indirect measure of ventilation. Another limitation is that the absorption of oxygen by circulating blood removes it from the lung unit, meaning there would inevitably be a difference between the wash-in and wash-out phases if they were measured. Additionally, the administration of 100% oxygen to patients, particularly those with advanced COPD, may alter the fundamental pulmonary physiology that we are attempting to measure (96).

Emerging imaging modalitiesOther Section

Optical coherence tomography (OCT)

OCT has emerged from the field of interventional pulmonology. It involves the measurement of lung structure from an endobronchial approach. Analogous to B-mode ultrasound but utilising light waves rather than sound waves, OCT involves the insertion of a near-infrared optical probe into the airway, with a sensor to detect back-scattered and reflected light waves. A detailed description of the physics of OCT is present in Huang’s seminal review of the topic (103). OCT images have sufficient resolution to distinguish between different tissue types within the airways, i.e., mucosa, sub-mucosa, lamina propria, cartilage, airway smooth muscle and alveoli. This ability of OCT can therefore potentially identify malignant tissue at the time of bronchoscopy, where the structural components of tissues are altered in their organisation, content and reflective properties (104).

Although there are few studies in subjects with COPD, OCT is ideally placed to measure the anatomical properties of small airways, being limited only by the physical reach of the probe and by the need for repeated measurements in different areas to obtain representative sampling. Miniaturised probes can be introduced down to the level of the terminal bronchiole (105,106). Coxson and colleagues demonstrated an excellent correlation between airway dimension measured by OCT and by CT (107). OCT may give more accurate measurement of airways size since, in this study, CT-measured dimensions tended to be larger than the OCT measurements. Furthermore, OCT airway dimensions measured at the 5^th generation bronchi showed a strong negative correlation with the subject’s FEV₁, and had greater discriminatory power for airflow obstruction than CT measurements (107). There was also an increase in %wall area and an increase the density of subepithelial structures in subjects with a lower FEV₁ (107). Kirby et al. (108) reported a strong negative correlation between airway wall area and FEV₁ in males COPD subjects but not in females, which is an interesting observation that may be relevant to the observed differences in disease behavior between the sexes .

Electrical impedance tomography (EIT)

As its name suggests, EIT measures differences in impedance to the flow of an electrical current through different tissues. A typical setup involves a set of surface electrodes, usually 16 to 32, positioned around a body structure. Through a pair of electrodes (the ‘drive pair’) a small current is applied. The potential difference between each pair of adjacent electrodes is then recorded, and hence the resistivity or impedance at that location can be determined. The process is repeated with each pair of electrodes acting as the drive pair, and a spatial map of resistivity is developed. This technique is ideally suited to pulmonary monitoring for several reasons. Firstly, the lungs, being filled with air, have naturally high impedance and are subject to large changes in volume during respiration. This gives a relatively large ‘swing’ in impedance that can be used to monitor breathing patterns and interventions. The change in electrical lung impedance is proportional to the change in gas content, which has been validated against other imaging modalities (111-113). Secondly, a decrease in impedance from initially high values could be used to detect focal consolidation/collapse or more diffuse changes in, for example, acute respiratory distress syndrome (ARDS). Thirdly, the short acquisition time provides enough temporal resolution for real-time monitoring of the lungs over long periods, as opposed to quasi-dynamic imaging of ventilation CT or nuclear medicine. Finally, being small and portable, EIT can be used in a variety of physical settings.

Part -b

1.

The cranium (skull) is the skeletal structure of the head that supports the face and protects the brain. It is subdivided into the facial bones and the brain case, or cranial vault . The facial bones underlie the facial structures, form the nasal cavity, enclose the eyeballs, and support the teeth of the upper and lower jaws. The rounded brain case surrounds and protects the brain and houses the middle and inner ear structures.

In the adult, the skull consists of 22 individual bones, 21 of which are immobile and united into a single unit. The 22nd bone is the mandible (lower jaw), which is the only moveable bone of the skull.

of the forehead. Below the orbit is the infraorbital foramen, which is the point of emergence for a sensory nerve that supplies the anterior face below the orbit.

blood supply in the brain :

bout fifteen percent (15%) of the daily cardiac output is utilized by the brain. Owing to the high oxygen and nutrient demand of the organ, it is supplied by two arterial systems:

• The anterior circuit is supplied by the internal carotid arteries
• The posterior circuit is supplied by the vertebrobasilar system.

The focus of this article will be to discuss the major arteries that supply the brain.

More details about the development, course and their target regions of the individual vessels can be found in their respective articles.

Key facts

Table quiz

Development	3rd - 7th gestational weeks
Anterior circulation	Internal carotid arteries Anterior cerebral arteries Anterior communicating arteries Middle cerebral arteries
Carotid artery	Branch of the common carotid artery Cincinnati classification and Newer 4 part classification Mnemonic (excludes C1): Please Let Children Consume Our Candy
Posterior circuit	Posterior cerebral arteries Posterior communicating arteries Vertebral arteries Basilar artery
Vertebral arteries	Branches: posterior inferior cerebellar artery (PICA), anterior and posterior spinal, meningeal and medullary arteries
Basilar arteries	Branches: Anterior inferior cerebellar, Superior cerebellar, Internal auditory (Labyrinthine). Becomes the posterior cerebral artery
Circle of Willis	Union of anterior and posterior circulation In the subarachnoid space, in the interpeduncular cistern Surrounds optic chiasm and infundibulum
Clinical Significance	Anterior circulation stroke Posterior circulation stroke

bone implant

Bone implants have to withstand considerable stress. Therefore an essential test must show whether the metal does suffer a reduction of stability during the intended production of a prosthesis, or if it maintains its strength. Heating for the purpose of binding a bioactive layer must be kept under critical limits to preserve the internal structure of the metal. The laser-induced process of fixing the bioceramic powder binds these small particles very effectively. A very significant property of the ultrashort pulses must be emphasized here. Shorter laser pulses cause an ablation only in a very thin surface layer. There is hardly any heat transfer into deeper layers underneath the ablated volume. One sometimes talks about ‘cold’ ablation. The immediate surrounding does not suffer much heating.

It must be investigated if the marginal (heat) influence of the ceramic powder fixation to the metal has any negative effect on the mechanical stability. One established method for studying the material strength is the rotating bending fatigue test. This statistical method applied to specially prepared samples (hourglass rods) is already described elsewhere (Symietz, 2012). A brief outline of the experiment and the results is given here. The samples were rods of medical grade Ti6Al4V (Merete Medical GmbH, Berlin, Germany) as shown in Fig. 4.13. The so-called hourglass rods have a reduced diameter in the middle, where they will break under too much stress. A set of 20 samples was necessary to approach the critical mechanical stress in steps. The rods were fastened into a device that allowed turning them around their symmetry axis with a frequency of 73.7 Hz. For each run, lasting for more than one day, a constant four-point bending moment was adjusted. The thinner central section of each rod was exposed to alternating positive and negative stress, with the maximum absolute value on the surface of this middle part. This material wear caused by alternating compression and tension simulates an ageing process of the metal. A final number of 10⁷ rotation cycles defines the desired survival lifetime of the samples. This is a step-by-step approach by adjusting a predetermined upper or lower stress level. The previous result (survival = unbroken rod, failure = broken rod) dictates the choice for the next experiment. Normally 20 rods are enough to find a stress value around which the individual test runs level off.