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Aneuploidy is found in 4% of cases of isolated holoprosencephaly but in 39% of cases if other abnormalities are present medications ok during pregnancy trusted 5 mg dulcolax. Itoccurs more often in cases of maternal diabetes (a 200-fold increased risk) and is also a commonly observed feature of numerous syndromes medicine ubrania discount generic dulcolax canada, including Pallister-Hall syndrome symptoms weight loss purchase dulcolax in india, Kallman syndrome 606 treatment syphilis purchase dulcolax 5 mg without a prescription, Meckel-Gruber syndrome, Vasadi syndrome, and camptomelic dysplasia. The prognosis for alobar and semilobar holopros encephaly is very poor, as most infants die at birth or within 1 year of life. If a prior infant had holoprosencephaly unrelated to karyotypic abnormalities, the estimated recurrence rate is 6%, although some families appear to exhibit either autosomal recessive (25% recurrence) or dominant (50%) inheritance. The shape of the skull may offer important clues about underlying fetal disorders. Some fetuses display a cross-sectional skull shape reminiscent of a lemon (the lemon sign), which results from bilateral frontoparietal narrowing of the skull. Fetuses with excessively round skull morphology, brachycephaly, are at in creased risk of trisomy 21. Hypoplasia of the facial bones may result in proportionately narrowed ante rior skull dimensions, giving the skull a strawberry shaped appearance (straw berry skull). Although fetuses with head circumferences less than the 10th centile usually have excellent outcomes, those with more severe restriction of head size, mi crocephaly, do not. Microcepahaly is strongly associated with adverse neonatal outcomes and is a clinically useful marker for underlying aneuploidy, hered itary conditions, in utero infection, teratogen exposure, and radiation injury. Twenty percent of microcephalic fetuses have karyotypic abnormalities and trisomy 13 is the most common chromosomal abnormality found. The posterior fossa view offers a cross-sectional assessment of the cisterna magna,cerebellum,andtheposteriornuchalfold,whichcanbemeasuredfrom this plane (Figure 4. The plane of imaging is highly angle dependent, and improper tangential images may yield falsely elevated cisterna depths of 13 mm or more. The cerebellum can be nicely visualized and the nuchal thickness measured in this same plane. The cisterna magna ranges from 1 to 10 mm in depth over gestational age from 15 to 36 weeks and from 4 to 10 mm at term. Decreased cisterna magna depths may result from herniation of the brainstem down the spinal canal, whichmayoccurinassociationwithneuraltubeabnormalities. Cisternamagna depths of less than 3 or 4 mm suggest the possibility of open neural tube defects Falx Calvarium A B Cisterna magna Cerebellum 4. Cisterna magna depths > 11 mm in rare cases may be a normal variant and sometimes result from inappropriate imaging with excessive angulation of the ultrasound imaging plane. Forty percent of fetuses with excessively deep cisterna magna have been found to be aneuploid (most with trisomy 18). Posterior fossa cysts are present in 10% of infants with trisomy 18, 15% of those with trisomy 13, 1% of those with trisomy 21, and in 6% of infants with triploidy. The cerebellum normally has a bilobed or dumb-bell shaped appearance, but in cases of neural tube abnormalities, it may assume a fused appearance similar in shape to a banana (the banana sign). Cerebellar transverse diameter varies with gestational age and can be affected by fetal growth retardation. The cerebellar vermis can also be viewed in a similar imaging plane but may not be easily imaged in many patients. Dandy-Walker malformations are characterized by partial or complete ab sence of the cerebellar vermis and a characteristic cystic dilation of the fourth ventricle often accompanied by hydrocephaly. The Dandy-Walker anomaly is associated with a variety of underlying conditions, including autosomal reces sive conditions such as Aicardi syndrome, Meckel-Gruber syndrome, Walker Warburgsyndrome;aneuploidy(trisomy18);infectionssuchastoxoplasmosis, cytomegalovirus, and rubella; maternal diabetes, exposure to compounds such as coumadin and ethanol, agenesis of the corpus callosum, porencephaly, and schizencephaly. Increased nuchal thickness is an important marker of aneuploidy and is perhaps the only commonly observed minor sonographic? In the second and third trimesters, the nuchal fold is best measured in the same plane used to evaluate the posterior fossa. Caremustbetakentoobtainanoptimalimagingplane,becauseestimates of the nuchal fold width and cisterna magna depth vary widely if inaccurate images are created. Inadequate angulation relative to the axial plane will re sult in falsely low estimates of these characteristics, while excessive angulation will result in falsely large estimations. In practice, the best estimates of these parameters will be obtained from images that optimally image the cerebellum. Nuchal thickness greater than 6 mm at 15?23 weeks gestation are associated with trisomy 21 and other aneuploidies and are also associated with increased risk for cardiovascular malformations (Bahado-Singh et al. Unfor tunately (for purposes of aneuploidy screening), nuchal thickness gradually increases over this range of gestational ages in normal pregnancies. It is optimally imaged in a sagittal plane with the fetal head in a neutral position (not? Unfortunately, measurements of this characteristic are very prone to opera tor variation, and this technical issue has limited the general applicability of early pregnancy nuchal thickness screening. The association be tween increased nuchal translucency and aneuploidy is also valid in multiple gestations. As a result, nuchal lucency screening offers a means of antenatal aneuploidy screening in multiple gestation not offered by standard serologic methods such as maternal serum triple or quadruple marker screening, which, for the most part, are confounded by problems engendered by assessing the risk of aneuploidy in two fetuses from the same pooled maternal serum sample. In chromosomally normal infants, other potential infectious causes such as toxoplasmosis, parvovirus, and coxsackievirus B should be considered. It occurs in about 1/6,000 pregnancies and usually presents as bilateral, asymmetric, thin-walled, often multiseptate cystic masses located posterior and lateral to the high cervical vertebrae. Cystic hygromas may represent normal developmental events but usually re sult from aberrant development due to aneuploidy or early infections. They are most commonly found in association with aneuploidy (monosomy X, trisomy 21, trisomy 18). Cystichygromasduetoaneuploidyorinfectionhaveahigh propensity for fetal demise in utero. Avarietyofothertumorsoftheneckareoccasionallyencountered,including thyroid goiter, hemangiomas, teratomas, branchial cleft cysts, lipomas,? Perhaps the most important of these from an obstetric perspective is fetal thyromegaly or goiter. The en larged thyroid usually presents as a solid, bilobed, homogenous mass in the anterior neck, and hydramnios (present in 30%) may occur due to impaired fetal swallowing. Delivery at a high-risk neonatal facility is recommended be cause of the high risk of airway obstruction at birth (Stocks et al. They result from a localized proliferation of vascular tissue that rarely presents as a discrete fetal neck mass. They usually have a complex sonographic ap pearance with many small vascular channels and an almost solid appearance. Close surveillance for hydrops, skin edema, ascites, and pleural effusion should be maintained, and newer methods of fetal cardiac assessment may be considered. Falken sammer and Huhta recently described the use of the Tei-index (isovolumetric time/ejection time) and a cardiac function score, which assessed 5 factors re lated to cardiac function (presence of hydrops, venous Doppler? Using these indices and serial evaluations, it may be possible to identify early fetal cardiac dysfunction, and institute therapy before overt failure is present. They are usually uni lateral and situated in the anterolateral portion of the neck, often presenting as cystic lesions that enlarge and increase in complexity over the course of preg nancy, sometimes achieving 8?10 cm in diameter. Untreated cervical teratomas have high mortality rates (80?100%), but oper ative mortality of 9?15% is not negligible. The presence of large neck masses may limit mobility of the neck, which in turn may contradict breech delivery. Large masses may also necessitate consideration of cesarean delivery for vertex presenting infants, as has been described for goiter and hemangiomas (Stocks et al. Clefting of the upper lip is relatively easy to assess, while abnormalities of the palate are more dif? If major chro mosomal abnormalities are suspected, care should be taken to exclude the pos sibility of central facial abnormalities. Measurement of inter and intraorbital diameters and careful evaluation of the nose and mouth are recommended. Fa cial clefts not due to underlying syndromic causes occur in about 1/800 births. They occur more often in males (60?80% male predominance) and are asso ciated with advanced maternal age. They occur more commonly in Asians and Native Americans and are uncommon in blacks. The association between facial clefts and aneuploidy varies by the timing of the evaluation.
More than 984 events involving disease investigations in wildlife were added to medicine 773 cheap dulcolax online mastercard the national database of Wildlife Australia uses the data collated in the National Animal Health Australia in 2014 medicine 6 year in us order dulcolax 5mg overnight delivery. A total of 335 bats were tested for essential for supporting trade in animal commodities medications knowledge best dulcolax 5mg. This is a higher Since they were frst detected in Queensland in 2007 treatment yeast uti order dulcolax 5mg online, proportion than in previous years. Research and development projects that started in factors afecting which bats have been submitted under the Asian Honey Bee Transition to Management for testing. In 2014, no wild bird mortality events were attributed to the aim is to reduce the incidence and impact of bee avian infuenza or West Nile virus. Surveillance activities pests and diseases, and build capacity to apply research in wild birds continue to fnd evidence of a wide range of fndings through extension and education. The following signifcant notifcations were made in 2014: Three mass mortality events involving eastern grey. Findings from the and one mare that aborted a full-term foal on a review are currently being considered by the Screw property in Queensland. Terrestrial animal disease surveillance and monitoring Improvements were made during 2014 to the National Bee Pest Surveillance Program, which is an early warning Chapter 3 describes disease surveillance and monitoring system to detect new incursions of pest bees and exotic activities under government and nongovernment bee pests. The improvements included increasing the programs that operate at the national level. These number of high-risk ports covered by surveillance programs are managed by Animal Health Australia, activities and the level of surveillance at some existing Wildlife Health Australia, and the Australian, state and ports, deploying remote surveillance hives (catch boxes territory governments. The animal health strategy, the Northern Australia Quarantine Strategy is an which will be completed in 2015, will detail the integrated program of active and passive disease surveillance and diagnostic objectives to support surveillance in northern Australia. This project is xii Animal Health in Australia 2014 an efective way of maintaining a baseline understanding advice on measures to reduce the occurrence of avian of animal health in these remote areas. Discussions with Japanese encephalitis included use of a novel method industry are now in progress to identify and implement that allows molecular testing of excreted saliva from the most practical ways to minimise the risk of avian mosquitoes (the primary vectors of the virus); no infuenza infection in the poultry industries. This result in signifcant gains in trade through simplifcation corresponds with the emergency response deeds that of customs procedures. Australia has in place for terrestrial animal and Free trade agreements have been signed between plant diseases. Revisions the Department of Agriculture has negotiated new of four manuals commenced in 2014 for the diseases market access for a range of animal, animal product viral encephalopathy and retinopathy, whirling disease, and food exports, and maintained access to signifcant withering syndrome of abalone and crayfsh plague. New South Wales manages the disease through movement controls Consumer protection on farmed oysters, oyster farming infrastructure and A number of Australian agencies at the national, and equipment from afected areas. In September 2014, the state and territory levels cooperate to ensure the safety New South Wales Government released the Pacifc Oyster of the Australian domestic food supply and the safety of Mortality Syndrome Incursion Response Policy, which sets Australian food exports. Chapter 7 describes activities to out response actions and responsibilities that will apply in ensure that locally produced foods are safe for consumers. The Australian Government Department of Health the Regional Profciency Testing Program for Aquatic monitors communicable diseases, including foodborne Animal Disease Laboratories in Asia, funded by the diseases, to provide early warning of any potential Department of Agriculture, was completed in late 2014. The program resulted in signifcant improvements in the accuracy of testing to diagnose important aquatic animal the National Residue Survey in the Department of diseases in participating laboratories. The Australian Australia is an active participant in the Codex Alimentarius Government adopts a risk-based approach across the system, providing expertise for a number of Codex biosecurity continuum to manage the pest and disease committees, and chairing the Codex Committee on Food threat from imports. The Collaborating Centre is cooperating with partners in Southeast Asia to build animal welfare science capacity in Each state and territory is responsible for implementing the region through a training program. These At a national level, the Animal Welfare Task Group is activities occur in three main categories: continuing to develop nationally consistent standards and guidelines for the welfare of livestock, based on. Various of cattle and sheep standards and guidelines is well other activities took place to develop skills in animal advanced, and the documents are now ready for disease surveillance and response, and raise public consideration by governments. The Department of Agriculture continued its progress on various aspects of the draft national pest and disease surveys of Norfolk Island. Discussions began on 2014, which aligns the goal of poverty reduction with a review of the Model code of practice for the welfare of the pursuit of economic growth in the region. Australia animals: domestic poultry, which will form the basis of the supports partner governments in building surveillance development of Australian animal welfare standards and systems and improving their ability to respond to guidelines for poultry. The strategy partner countries to use multidisciplinary approaches encourages co-investment and collaboration on a national to solve problems in smallholder animal health and basis to improve the efcient use of research, development production. The fnal report Mekong region, the Philippines, Papua New Guinea on a project to monitor public attitudes to animal welfare and southern Africa. Research and development the Minister for Agriculture has announced reforms to Chapter 10 provides a snapshot of Australian research the Exporter Supply Chain Assurance System for live in livestock health during 2014. Overview xvxv Animal Health Australia xvi Animal Health in Australia 2014 Chapter 1 Organisation of the animal health system Efective national surveillance and control of animal diseases in Australia requires cooperative partnerships among the government agencies, organisations, commercial companies and individuals who are involved in animal industries. The Australian Government advises on and coordinates animal health policy at a national level. Under the Australian constitution, the individual state and territory governments are responsible for animal health matters within their boundaries. Such matters include disease surveillance and control, emergency preparedness and response, chemical residues in animal products, livestock identifcation and traceability, and animal welfare. This allows consultation between government and industry to determine national animal health priorities. The livestock industries participate in policy development, support targeted animal health activities and contribute to emergency responses. Links are maintained with partner human health agencies, particularly with regard to zoonoses and food safety. The Australian Government Department of Agriculture is actively represented Organisation of the animal health system 11 Table 1. These projects improve animal and human consistent animal welfare standards and guidelines for health, biosecurity, livestock welfare, productivity, market sheep and cattle. The committees provide their advice and support to senior areas of government through national departmental and ministerial forums for agriculture that is, the Agriculture Senior Ofcials Committee and the Agriculture Ministers? Forum, respectively. It comprises the Prime Minister, state and territory premiers and chief ministers, and the president in Australia. With a national focus on animal academia, industry and the private sector may also be health, welfare and biosecurity issues, the company invited to participate. The organisations and service providers; a number of other New Zealand Government was also a member. The current maintained professional and technical standards for membership is shown in Table 1. The company has established a number of formal health system come together as needed. An industry consensus can then be brought committees and to the Members? Forum for broader consideration by all organisations members of the company. Australian Capital Territory Australian Dairy Farmers Ltd Northern Territory Australian Duck Meat Association Inc. State of New South Wales Australian Egg Corporation Ltd State of Queensland Australian Honey Bee Industry Council Inc. State of Victoria Australian Pork Ltd State of Western Australia Cattle Council of Australia Inc. It is under the National Organochlorine Residue Management supported by a range of principles and initiatives that Program, the National Antimicrobial Residue Minimisation form a roadmap for the future. Program, the Targeted Antimicrobial Residue Testing Program and the Sheep Targeted Antimicrobial Residue Testing Program. This reputation has signifcant through national programs; and long-term management economic, environmental and community benefts for of pests and diseases established in Australia. This will lead to a more modern system that is responsive and targeted in a changing the Biosecurity Bill 2014 and its supporting Bills (the global trading environment. When Australian governments, primary industries and other passed, the biosecurity legislation will replace the stakeholders work closely together to prevent, detect, Quarantine Act 1908 as the primary legislative means for control and manage pest and disease outbreaks, and the Australian Government to manage biosecurity risks. To do this efectively, jurisdictions, framework to manage the risk of pests and diseases industries and stakeholders use consistent and entering Australian territory and causing harm to animal, collaborative approaches. These will improve the sharing of data animal health services and information between jurisdictions, and the Under the Australian constitution, the Australian efectiveness of emergency responses. They will also Government is responsible for quarantine and support market access for Australian agricultural, international animal health matters, including disease fsheries, food and forestry industries.
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Facial anomalies in clude hypoplasia of the malar medications and mothers milk discount dulcolax 5mg without prescription, maxillary medicine naproxen buy dulcolax 5mg otc, or mandibular regions (especially the ramus and condyle of the mandible and temporomandibular joint) symptoms 9dp5dt dulcolax 5mg on line, macros tomia medications jfk was on discount 5 mg dulcolax with amex, and hypoplasia of facial muscles. Infant with hyper telorism, high forehead, beak nose, and syn dactyly of second and third fingers. Cutaneous syndactyly between 2nd and 3rd fingers, brachydactyly with short 4th metacarpal and clinodactyly 14. Facial asymmetry, prominent forehead, down ward slanting of eyes, and a preauricular appendage (arrow). Mandibular hypoplasia, prominent forehead and varying types of malformed displaced pinnae Note epibulbar dermoids, facial asymmetry, Facial asymmetry, Bilateral epibulbar dermoids frontal bossing, mandibular hypoplasia eye and ear anomalies with downward slant of palpebral fissures and preauricular appendages 14. Cleidocranial dysplasia this is an autosomal dominant mutation with marked variability. An intramembranous bone defect results in lesions of the skull calvaria, viscerocranium(face),andclavicles. Mandibulofacial Dysostosis (Treacher Collins Syndrome) this syndrome can be recognized at birth due to a typical facial appearance (Figures 14. The eyes may show several anomalies which include the following: antimongoloid obliquity of the palpebral? The nose appears large due to a lack of malar development, while the nares are often narrow and the A B 14. First and second cartilage, dominant arch artery occlusion malleus, incus, Abnormal ear ossicles chromosome External ear hillocks Auditory tube, gene cloned acoustic tympanum meatus Stapes, hyoid (part of), styloid process, stapedial artery Cervical sinus Tonsillar Canal atresia/hypoplasia Hyoid (majority), fossa proximal third of Cervical sinus internal carotid artery Parathyroid 3, thymus 3 Thyroid and laryngeal cartilages. Degrees of lateral downward slant of palpebral Malformed ears, ear tags, micrognathia, large fissures, coloboma of outer portion lower lids, appearing nose with narrow nares malformed ears and facial asymmetry 14. Micrognathia is almost always present; other oral manifestations include cleft palate (30%), high-arched palate, dental malocclusion, and unilateral or less often bilateral macrostomia. Some patients have an absence of the external auditory canal or ossicle defects associated with conductive deafness. Holoprosencephaly (See Chromosome Chapter) A spectrum of malformations of the face re? The most severe manifestation of the condition is cyclopia, within which a range of expressions appear. Holo prosencephaly is a component part of trisomy 13 syndrome and other chromosomal defects and may be seen in diabetic embryopathy. The most frequent craniofacial anomalies arecleftsoftheupperlipandpalatethatcannowbediagnosed prenatally (Figures 14. Bilateral clefting of the face with rudimentary premaxilla facial structures and extend into the orbits. On left, cleft extends to inner canthus and left nostril and lateral cleft at angle of mouth. Ear Anomalies the external ear may display a wide spectrum of anomalies from complete ab sence to multiple tags (Figures 14. Ear anomalies may be a com ponent part of malformation syndromes or sequences such as the DiGeorge sequence. Abnormal ears: (A) Preauricular tag-frequently contains core of cartilage represents an accessory auricular hillock. Helix meets the cranium (arrow) at a level below the horizontal plane with the corner of orbit. It is important to appreciate that in utero constraint deforma tion of the head may temporarily distort the usual landmarks. Facial Clefts Ultrasonography Non-syndromic facial clefting occurs in 1/800 births. Terms used in the description of bone dysplasias according to the defect in collagen are shown in Table 15. Prenatal diagnosis has been made in most of the lethal forms of ostechondrodysplasia (Table 15. For most convenience in diagnosis they can be divided into the following groups: Osteochondrodysplasias with platyspondyly Osteochondrodysplasias with short trunk Short rib osteochondrodysplasias Osteochondrodysplasias with defective bone density Miscellaneous group Osteochondrodysplasias with Platyspondyly (Table 15. Histopathologically the physeal growth zones are usually disorganized and may be retarded, but the resting cartilage is mostly unremarkable. It is a new dominant mutation; however, gonadal mosaicism proliferative cartilage may result in variable expression and reduced penetrance with a small risk of. Microscopically the zone of resting cartilage is hypercellular in the Torrance chondrocytes in hypertrophic zone and Lutow types with normal columnation of chondrocytes in the Torrance Radiological features anddisorganizedcolumnsintheLutowtype. Three genetic forms exist: autosomal recessive nonlethal type, dominant nonlethal type, and lethal type with possibly autosomal recessive inheritance. The trunk and limbs are short with bulbous enlargement of the joints and frequently a coccygeal tail. Platyspondyly is more severe than thanatophoric dysplasia and the ribs are short with? Schneckenbecken (snail pelvis), an autosomal recessive condition, is char acterized by a snail-like pelvis and short limbs. There is hypercellularity of the resting and proliferating cartilage, the lacunar spaces are inapparent, and the intercellular matrix is relatively inapparent. Reduced columnation and hyper vascularity are seen in the proliferating cartilage. Ra diologically, the vertebral bodies show variable abnormalities, ranging from their complete absence to vertebrae that are small, oval, or variable in size. Death in utero or shortly after birth retarded ossification Lack of columnization. Hydropic appearance large head, short In type I, ribs thinner with multiple Irregular physeal-metaphyseal junction. An occipital encephalocele has been associated with type 1A and the infant frequently is born prematurely and with fetal hydrops. Prominent eyes, cleft palate, hearing loss, myopia, and coronal clefting of the lumbar vertebrae are characteris tic. Radiologicallytherearebroadlimbswithlargemetaphyses,whichareslightly irregular; short ribs and pyriform vertebral bodies on lateral view; and abnor mal pelvic bones. The largest cisterna with finely granular material corresponds to an inclusion in (C). Infants have a severely narrowed chest with mild shortening of the limbs, polydactyly, congenital heart disease, and abnormal nails and teeth (Figure 15. Death occurs shortly after birth due to respiratory failure because of the narrow chest. Postaxial polydactyly and ectodermal dysplasia are present; however, some cases are without polydactyly. Prominent eyeballs, blue sclerae Rarely survive cystic changes long Normal calcification of chondroid columns. It is due to a new autosomal dominant mutation with an abnormality in secretion of type I procollagen (Figure 15. Pathology the collagen defect results in a defect of production of osteoid and results in calci? Abnor mal bony spicules in the cortex are composed of primitive woven bone and excessive? The bones are well preserved and show innumerable fractures involving all tubular bones and ribs. Phospho ethanolamine and inorganic pyrophosphate in the blood and urine are in creased. Pathology Broad columns of unmineralized cartilage covered by poorly mineralized osteoid seams. Physeal growth zone in the neonatal period is widened and thickened, hyper cellular, and disorderly arranged; alkaline phosphatase in this area is markedly reduced. Sites of reaction to possible metabolic injury Cancellous bone formed directly on resting cartilage Hypertelorism Sparse, coarse scalp hair Cataracts (25%) Prominent forehead Saddle nose Anteverted nares Hyperkeratosis Micrognathia and erythema of skin in infancy Microcephaly Prominent forehead Kypho Cataracts(75%) scoliosis Saddle nose Long Lymphedema Conradi limbs of cheeks Hunermann Contrac dominant type tures of Proximal elbows, shortening knees, of limbs Rhizomelic, recessive type hips with shortening of humerus Calcification about Large and calcification about elbow spine and epiphyses skin in infant pores Eczematoid dermatitis A B C D E 15. Multinucleatedgiantchondrocytes present in atelosteogenesis type I and boomerang dysplasia. Disorganizationandshorteninginproliferativeand hypertrophic zones and reduced cellularity of growth plate within myxoid foci.
In order to symptoms of anxiety cheap dulcolax 5 mg without a prescription consider also physico-chemical criteria in binding site detection the surface of the protein can be scanned with fragments of ligands with subsequent calculation of their complementarity treatment 5th metatarsal avulsion fracture buy dulcolax 5 mg on line. Another approach to symptoms after miscarriage buy dulcolax overnight get an idea about potential active sites can be achieved by comparing the query protein with homologues medications jejunostomy tube order dulcolax 5mg online, as proteins with related function share similar binding sites. As soon as the binding site is known, it has to be characterized in order to get information about specific binding possibilities through non-covalent interactions. To detect these hot spots atom probes, ligand fragments or whole small molecules are positioned inside the binding pocket. After energy minimization those probes cluster at certain local minima defining the hot spots (Caflisch et al. Ideally it should therefore consider all possible degrees of freedom, which leads to higher accuracy. However, due to limitations regarding computer power, this is penalized in favor of higher speed by reducing the number of the degrees of freedom (Sousa et al. Although in protein-protein docking the rigid-body approximation is still applied (Kuntz et al. Approaches that try to explore all degrees of freedom of the ligand systematically comprise conformational search methods, fragmentation methods or database methods. By applying Molecular Modeling and Simulation of Membrane Transport Proteins 379 conformational search methods, every rotatable bond of the ligand is rotated in fixed increments. As this can easily lead to a combinatorial explosion, this technique can only be applied for small or rigid ligands. More prevalently used are the so-called fragmentation methods that place fragments of the ligand in the binding pocket, which are subsequently fused. Depending on the fragmentation and placing of the ligand place and join and incremental approaches can be distinguished. A computationally efficient way to search for possible orientations forms the database method. For this protocol a conformational library of the ligand is prepared which is docked rigidly into the binding site. Besides systematic search algorithms there are programs that prefer stochastic principles for binding mode prediction. At this the flexibility of the ligand is provided by random conformational changes that are either kept or rejected on basis of a direct evaluation of the conformation. With this optimizing procedure a random population of possible ligand poses is generated, where the characteristics (degrees of freedom) of each are stored in its genetic code (chromosome). By applying genetic operations, like cross-over or mutation, new poses are generated and subsequently scored. Depending on this fitness score the pose is either rejected or it replaces the least fit member of the population. This procedure is conducted over thousands of cycles w hich ends up in highly optim ized ligand orientations. Another possibility to consider ligand flexibility is presented by molecular dynamics simulation of the ligand in the binding pocket. However, this is mainly used in combination with other search algorithms (Kitchen et al. In the last years not only the flexibility of the ligand but also protein movements due to ligand binding gained more and more importance (B-Rao et al. Although it is known that some proteins undergo large structural changes, even domain rearrangements, upon ligand binding, by now it is not possible to cover that in reasonable time and effort. However, since docking a ligand into the right conformation of the binding site is extremely important for the quality of the resulting orientations, efficient workarounds have been developed. Soft docking is one possibility to account small movements of the protein side chains during docking (Jiang & Kim, 1991). For this technique soft potentials are applied on certain side chain atoms in the binding pocket, which therefore tolerate overlap with ligand atoms. The merit of this technique is the easy implementation, as only scoring parameters have to be adapted. On the other hand only small changes can be considered and there might be a bias towards the starting structure. With the help of rotamer libraries, movements of side chains are included in the search algorithm (Leach, 1994). Depending on the size of the library this method calls on moderate computational power and is able to adapt to certain ligand conformations. Nevertheless, as the backbone is kept rigid large structural movements cannot be covered. As this approach is extremely costly, the more efficient method of ensemble docking should be used preferentially. Therefore an average receptor grid is generated and used for docking (Knegtel et al. A hybrid technique that is commonly used to encounter protein flexibility is the induced fit docking protocol of the Schrodinger Suite (Sherman et al. This method turns major attention on the ligand-induced conformational changes of the protein residues surrounding the binding site. Therefore, the ligand is docked into the rigid binding pocket, amino acid residues that are within a certain radius of the resulting poses are removed and rebuilt using the Schrodinger homology modeling program Prime. After energy minimization of the complex the ligand is redocked into the modified binding pocket. In order to understand the interaction between a defined molecule and the target protein the scoring function needs to be able to identify the true pose among the plethora of orientations, generated by the search algorithm. For lead optimization in particular a scoring function should correctly determine the affinity between the ligand and the protein. However, for virtual screening of large compound databases scoring should provide correct ranking. As there are still limitations regarding computer power, the right balance between accuracy and speed has to be chosen, which is strongly dependent on the field of application (reviewed in (Huang et al. Force field based scoring functions use terms that describe the free energy of binding for evaluating binding poses. Furthermore the accuracy of these methods depends on their treatment of the solvent. More accurate techniques, like thermodynamic integration or free energy pertubation, treat water molecules explicitly. However all of these methods are still not applicable for virtual screening as they are computationally too expensive. They assess the quality of binding by a number of weighted terms that are derived by fitting data of complexes to known affinities (Bohm, 1994; Bohm, 1998). Numerous commonly used scoring functions belong to this group, including ChemScore (Eldridge et al. Nevertheless, a disadvantage of this method would be the dependence on the training set, as complexes with binding affinity are essential. Molecular Modeling and Simulation of Membrane Transport Proteins 381 Thus, knowledge-based scoring functions may be preferred in this regard. These scoring functions make use of the statistical occurrence of protein-ligand interactions of complex databases. In contrast to empirical functions they do not aim at reproducing binding affinities, but experimentally determined structures, wherefore a much larger training set can be used (Tanaka & Scheraga, 1976). As the choice of the scoring function strongly depends on the research query, the combination of several functions, so-called consensus scoring, has been suggested (Charifson et al. In order to be able to allow for a sufficient comprehension of the dynamics of the transport protein, we can not only rely on experimental techniques. In addition, biomolecular simulations can provide a detailed description of particles in motion as a function of time. Thus, they are an important tool for understanding the physical basis of the structure and function of proteins, and biological macromolecules in general. However, experimental validation should always serve to test the accuracy of the calculated results and also to provide a basis for improving the methodology (Karplus & McCammon, 2002). It is almost 35 years ago, since for the first time McCommon, Gelin and Karplus have studied the dynamics of the pancreatic trypsin inhibitor by solving the equations of motion for the atoms with an empirical potential energy function (McCammon et al. In this very beginning of Molecular Dynamics simulations, the calculations were still restricted to the picosecond timescale. The interaction of the atoms is described by the potential energy function of the given force field [e.