G. William Henry, MD

• Professor of Pediatrics
• Division of Pediatric Cardiology
• The North Carolina Children? Heart Center
• University of North Carolina School of Medicine
• Chapel Hill, North Carolina

The visual cortex is therefore divided into many small regions anxiety 39 weeks pregnant discount 25mg phenergan free shipping, or columns anxiety symptoms vibration cheap phenergan 25mg without a prescription, that extend from the pial surface to the white matter and code the various angles that a linear stimulus might take anxiety test cheap phenergan 25mg without prescription. This columnar organization is repeated for each point on the retina as it is mapped onto the visual cortex anxiety images buy cheap phenergan. These columns are critical to stereopsis anxiety attacks symptoms treatment discount phenergan 25mg online, one of the ways in which depth is perceived in the visual world anxiety early pregnancy order phenergan 25 mg on line. This can be verified by pointing your finger at an object in your immediate environment and closing first one eye and then the other. In one cortical ocular dominance column, all simple, complex, and hypercomplex cells have a stronger response when the optimal stimulus is presented to one eye. The relationship between ocular dominance columns and orientation columns is normally depicted as if they were arranged at right angles to each other, although their exact relationship is probably not so simple. A collection of orientation columns in which the preferred stimulus orientation rotates through 180 degrees occupies about 800 m. The establishment of the neural connections in ocular dominance columns occurs after birth and requires proper visual stimulation in both eyes to develop normally. If disorders of vision such as strabismus, amblyopia, or congenital cataracts prevent the formation of simultaneous, superimposed, sharply focused images in both eyes during the early years of life, the neural connections that form the basis of the ocular dominance columns do not develop normally and the individual will not be able to experience stereopsis, although other aspects of vision may be normal or nearly normal. Using the neural mechanisms described previously, the visual system assembles progressively more complex representations of the visual world, beginning with tiny dots in the retina that are translated into lines and areas of light and dark in primary visual cortex and then into more and more sophisticated representations in visual association cortex (see next). For additional information on the processing of neural signals in the visual system, see the list of suggested readings. At some point, the synaptic connections made during the competition phase become permanent, the lateral geniculate neurons that lost the competition are permanently shut out, and binocular vision cannot be regained. Once the neural connections are established successfully, later disruption of visual input does not have a marked effect on the synaptic efficiency of the input to the visual cortex. However, what happens in the primary visual cortex is only a first step in the conversion of an image on the retina into a psychological perception. Many additional regions of the brain, generally termed visual association cortex and multimodal association cortex (see Chapter 32), participate directly or indirectly in this process. One of the surprising features of the visual system is that different aspects of the visual experience are processed by different regions of visual association cortex. One feature of visual processing that contributes to the parcellation of different aspects of the overall perception has already been introduced. The ganglion cells in the retina that project to the parvocellular (P) layers of the lateral geniculate nucleus are most sensitive to small, stationary stimuli and are concentrated in the central region of the retina. These cells are the origin of a pathway, or a "stream of processing," that is specialized at every level for the processing of the finely detailed, high-resolution aspects of vision, the aspects necessary to recognize an object, a word, or a face in the visual environment. A second general stream of processing originates in the retinal ganglion cells that project to the magnocellular (M) layers of the lateral geniculate. These ganglion cells are most sensitive to moving stimuli and to relatively large areas of light and dark and are more common in the peripheral retina. This pathway is specialized for the detection and analysis of movement in the environment and also for the spatial localization of objects in the environment. Curiously, it is possible for damage in this pathway, particularly in the parietal association cortex, to render a person unable to judge which of two objects is closer to him, although he has no difficulty in recognizing what the objects are (see Chapter 32). Starting in area 18, the M and P pathways that originate in the respective retinal ganglion cells diverge. Up to this level, both of these pathways, or streams of processing, have been located in the same general regions: M and P cells coexist in the retina, the lateral geniculate nucleus, and area 17, even though they process separate streams of information. The P stream proceeds from the V2 subregion to the V4 subregion of Brodmann area 19 and from there to the inferior temporal cortex (area 37). In fact, starting in the lateral geniculate nucleus, form and color information is carried by two separate portions of the P stream. The portion that subserves form perception makes use of the small receptive fields and consequent high acuity of the P ganglion cells. The color-opponent receptive fields of these ganglion cells form the basis for color perception, but these signals are relayed by a different subset of lateral geniculate neurons. Lateral (A) and medial (B) views of the cerebral cortex show some of the cortical areas (using Brodmann numbers) involved in the processing of visual input. Area 18 is divided into V2 and V3 subregions on the basis of its cortical connections. The magnocellular pathway (on the left) is sometimes termed the dorsal stream of processing, or the where pathway. The parvocellular pathway (on the right) is sometimes termed the ventral stream of processing, or the what pathway. For example, the process of perception seems to be anatomically distinct from the process of attaching meaning to what we see. Thus an apperceptive agnosia, in which the patient cannot identify objects because of a perceptual deficit, is a separate entity from an associative agnosia, in which the patient can perceive the object, face, or photograph but cannot attach any meaning to it. This latter phenomenon was described by Teuber as "percepts stripped of their meaning. Thus lesions in areas 18, 20, and 21 of the left (dominant) hemisphere typically result in object agnosia, in which the patient is unable to recognize. Lesions in these areas in the right (nondominant) hemisphere produce agnosia for drawings of objects. Smaller bilateral lesions in these areas, especially in the fusiform gyrus, may produce prosopagnosia, the inability to recognize faces. The patient can see the face and recognize it as a face but cannot distinguish one face from another, even the faces of old friends and family members. Balint syndrome results from bilateral lesions in the parietooccipital junction region. It consists of impairment of voluntary eye movements (reflex eye movements are preserved) and optic ataxia (inaccurate eye movements related to visual-motor coordination). Another dissociation of functions that we normally think of as linked occurs in the phenomenon of alexia without agraphia. In this syndrome, affected persons can write but cannot read what they have written (or what anyone else has written). A lesion of the splenium of the corpus callosum, carrying visual information from one visual cortex to another, combined with damage to the adjacent occipital region can produce this syndrome, which usually (but not always) occurs in conjunction with a homonymous hemianopia. The pattern of ocular dominance columns in macaque visual cortex revealed by a reduced silver stain. Henkel Overview-306 Properties of Sound Waves and Hearing-306 Processing of Sound: the Ear-307 External (Outer) Ear-307 Middle Ear-307 Conduction Deafness-307 Inner Ear: Structure of the Cochlea-307 Mechanoelectrical Transduction-309 Tuning of the Cochlea-310 Primary Afferent Innervation and Function-310 Sensorineural Deafness-310 Weber and Rinne Tests-311 Overview of Central Auditory Pathways-311 Vascular Supply of the Auditory Brainstem and Cortex-312 Brainstem Auditory Nuclei and Pathways-313 Cochlear Nuclei-313 Superior Olivary Complex-314 Lateral Lemniscus and Its Nuclei-315 Inferior Colliculus-315 Medial Geniculate Nucleus-317 Central Deafness-317 Auditory and Related Association Cortices-317 Descending Auditory Pathways-318 Olivocochlear Bundle-318 Middle Ear Reflex-318 Acoustic Startle Reflex, Orientation, and Attention-319 with other signs and symptoms. These three types of hearing losses are considered in more detail when we discuss the external and middle ear, the cochlea and cochlear nerve, and the central auditory pathways, respectively. To understand the neurophysiologic and audiologic methods used in assessing peripheral and central auditory disorders, it is essential to understand the structure and function of the cochlea and central auditory pathways. In combination with vision and the ability to speak, it contributes, in a significant way, to the quality of life. In our daily routine, we unconsciously sort out meaningful sounds from background noise, localize the source of sounds, and react (many times in a reflex mode) to unexpected sounds. About 12% of people in the general population experience a diminution or loss of hearing during their lifetime, which in some cases may represent a significant disability. Injury to elements of the peripheral apparatus, such as the ear ossicles, may result in conductive deafness. Alternatively, damage to the cochlea or the cochlear portion of the eighth cranial nerve may result in sensorineural (nerve) deafness. When central auditory pathways are injured, the apparent hearing dysfunction (central deafness) is usually combined 306 Complex sounds are mixtures of pure tones that are either harmonically related, thus having pitch, or that are randomly related and therefore called noise. The cochlear apparatus is designed to analyze sounds by separating complex waveforms into their individual frequency components. The time interval between two peaks is the period, the distance traveled is the wavelength, and the number of cycles per second is the frequency. The normal frequency range for human hearing is commonly described as between 20 and 20,000 Hz. Most human speech takes place in the range of 100 to 8000 Hz, and the most sensitive part of the range is between 1000 and 4000 Hz. Exposure to loud noise can result in selective hearing loss for certain frequencies, and normal aging may reduce the range. The hearing apparatus is exquisitely sensitive to sound intensity (perceived as loudness) over an enormous dynamic range. Intensity is related to a measure of sound pressure level at the tympanic membrane and is usually expressed on a logarithmic scale in units called decibels (dB). A sound that is 10 times more intense than a just audible sound is said to have a 10-dB sound level, and a sound one million times greater, 60-dB sound pressure level. Other common examples of noises above 120 dB that may cause varying degrees of discomfort include rock concerts, thunderclaps, firecrackers, and jet engines. The brain derives the location of a sound by computing differences in the shape, timing, and intensity of the waveforms that reach each ear. Thus interaural time and intensity differences are related to the angle between the direction in which the head is pointing and the direction of the sound source. Interaural time differences are more important for localizing low-frequency sounds, whereas interaural intensity differences are more important for localizing high-frequency sounds. The stiffness of the ossicle chain can also be modified by two muscles of the middle ear, the tensor tympani and stapedius muscles (middle ear reflex). Diseases such as otosclerosis and otitis media result in conductive hearing loss by affecting the efficiency of the ossicle movement. Otosclerosis, the cause of middle ear conductive hearing loss in about half of cases, may be an inherited disease and is characterized by tissue overgrowth and resultant fixation of the stapes in the oval window. Otitis media is an inflammation of the middle ear and may be accompanied by the accumulation of pus or exudate. In addition, fractures of the temporal bone with direct damage to the ossicles, or indirect damage by bleeding into the middle ear, may result in a conduction deafness. Lower panel shows that the arrival of a tone at right (D1) ear and left (D2) ear is affected by the distance traveled and shadowing effect of the head (center panel) when the source of the sound is displaced from the midline. A conductive deafness is a deficit related to an obstructed, or altered, transmission of sound to the tympanic membrane or through the ossicle chain of the middle ear. For example, damage to the pinna results in a failure of sound waves to be properly conducted to the auditory meatus. The deficit experienced by the patient may range from decreased hearing to total deafness in the affected ear. Depending on the cause, conduction deafness may resolve with medication or by removal of the obstruction. Resonance features of the pinna and meatus enhance some frequencies more than others in a direction-dependent fashion. For example, sounds coming toward the back of the head are baffled compared with those coming toward the side of the head. Monaural (single-ear) localization depends on such cues, and accuracy in localizing sound is impaired by damage to the pinna. Sounds are transmitted across the space from the tympanic membrane to the fluid-filled inner ear by a chain of three bony ossicles: the malleus, incus, and stapes. On one end of this chain, the arm of the malleus is attached to the tympanic membrane, and at the other end, the footplate of the stapes fits into the oval window at the interface with the fluid-filled vestibule of the inner ear. The three bones act as levers to reduce the magnitude of movements of the tympanic membrane while increasing their force at the oval window. In this way, air pressure waves striking the tympanic membrane result in plunger-like movements of the stapes against the oval window that have the necessary force to produce fluid pressure waves in the cochlea. Its main elements include a labyrinth of fluid-filled canals, specialized sensory epithelium of the organ of Corti, and neurons of the spiral ganglion with their peripheral and central axonal branches. The canals of the osseous and membranous labyrinth of the cochlea spiral two- and two-third turns from base to apex over a length of 34 mm. Uncoiled, the outer canals of the osseous labyrinth resemble a U-shaped tube and thus essentially are one canal. Scala tympani, the lower chamber in cross section, is continuous with the upper chamber at a hair pin curve, the helicotrema, at the apex of the cochlea. The fluid with which the vestibule and scala vestibuli and tympani are filled is perilymph. It comprises the membranous labyrinth and at its base is connected by ductus reuniens to the saccule of the vestibular membranous labyrinth. The basilar membrane, extending from the spiral osseous lamina of the modiolus (as from threads of a screw) to the spiral ligament at the outer wall of the canal, is the lower boundary separating the scala media from scala tympani below. The endolymph, which fills the cochlear duct, is elaborated by the cells and rich capillary bed of the stria vascularis. The blue and red lines represent the spiral course of scala vestibuli and scala tympani, respectively, from base to apex of the cochlea. C, the basilar membrane functions to separate waves of different frequencies within a sound. This membrane is narrow and stiff at its base and becomes wider and more flexible toward the apex, and the hair cell stereocilia increase correspondingly in height. These features "tune" the membrane so that each frequency of sound in the audible range will cause a wave in the basilar membrane that has its peak amplitude at a unique spot (near the base for high frequencies and near the apex for low frequencies). At this spot, the hair cells are excited most intensely, producing a peak in neural output. Note that the designation lateral or medial olivocochlear efferents refers to their origin in the superior olive, not to their target in the organ of Corti. It is composed of inner and outer hair cells, supporting cells, and the tectorial membrane.

They found that the combination of the two factors increased production of proteoglycans and Col2 over either monotherapy anxiety while driving cheap phenergan uk. It should be noted though that they did not include any single therapy controls to determine if the combination is empirically better than any single target alone anxiety symptoms in women buy cheap phenergan 25mg on-line. Importantly anxiety symptoms explained buy 25 mg phenergan fast delivery, gene therapy confers stable anxiety symptoms 2 25mg phenergan with mastercard, long-term expression of a therapeutic protein anxiety symptoms in males generic 25mg phenergan with amex, which otherwise would have to be frequently administered 0503 anxiety and mood disorders quiz order phenergan 25mg. Many gene therapy approaches have been evaluated in vitro and in vivo in small and large animal models, and a few have been tested in human clinical trials. Moreover, given the immense evaluation and optimization of various vectors in both in vivo and ex vivo contexts, researchers can now choose the most suitable gene transfer approach for their therapeutic needs. Although the number of clinical trials is still limited, data show that gene therapy for skeletal diseases is safe especially when 1. No gene therapy agents have so far been approved by regulatory agencies in the United states; however, Glybera (a treatment for lipoprotein lipase deficiency) was approved in europe in 2012 and two gene therapy drugs for cancer are on the market in China. More recently, strimvelis, the first ex vivo stem cell gene therapy for treatment of adenosine deaminase severe combined immunodeficiency, was approved by the european Commission in May 2016. At present, the gene therapy treatments that are the most likely to receive approval treat rare life-threatening diseases, whereas treatments for complex, less life-threatening diseases, such as those discussed here may take more time to gain approval as the regulatory agencies become more comfortable with the concept. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Toxicological comparison of e2a-deleted and first-generation adenoviral vectors expressing alpha1-antitrypsin after systemic delivery. Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of e2a wild type and e2a deleted vectors. Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors. A hemodynamic response to intravenous adenovirus vector particles is caused by systemic kupffer cell-mediated activation of endothelial cells. Development and characterization of novel empty adenovirus capsids and their impact on cellular gene expression. Phosphatidylserine is not the cell surface receptor for vesicular stomatitis virus. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Toward gene therapy for cystic fibrosis using a lentivirus pseudotyped with sendai virus envelopes. Novel hyaluronic acid-chitosan nanoparticles as non-viral gene delivery vectors targeting osteoarthritis. Repair of tissues by adult stem/progenitor cells (MsCs): controversies, myths, and changing paradigms. Integrin 1 gene therapy enhances in vitro creation of tissue-engineered cartilage under periodic mechanical stress. Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Cellular innate immunity and restriction of viral infection: implications for lentiviral gene therapy in human hematopoietic cells. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIl-beta. The evolution of adenoviral vectors through genetic and chemical surface modifications. Bone morphogenetic protein-2 nonviral gene therapy in a goat iliac crest model for bone formation. In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector. Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Human bone morphogenetic protein 2-transduced mesenchymal stem cells improve bone regeneration in a model of mandible distraction surgery. Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. Bone morphogenetic proteins 4 and 2/7 induce osteogenic differentiation of mouse skin derived fibroblast and dermal papilla cells. Regeneration of bone- and tendon/ligament-like tissues induced by gene transfer of bone morphogenetic protein-12 in a rat bone defect. Cellular and molecular mechanisms of accelerated fracture healing by CoX2 gene therapy: studies in a mouse model of multiple fractures. Microarray analysis of gene expression reveals that cyclo-oxygenase-2 gene therapy up-regulates hematopoiesis and down-regulates inflammation during endochondral bone fracture healing. Marrow stromal cell-based cyclooxygenase 2 ex vivo genetransfer strategy surprisingly lacks bone-regeneration effects and suppresses the bone-regeneration action of bone morphogenetic protein 4 in a mouse critical-sized calvarial defect model. Repair of critical-sized bone defects with anti-miR-31-expressing bone marrow stromal stem cells and poly(glycerol sebacate) scaffolds. Adeno-associated virus-mediated osteoprotegerin gene transfer protects against particulate polyethylene-induced osteolysis in a murine model. Adenoviral vector-mediated overexpression of osteoprotegerin accelerates osteointegration of titanium implants in ovariectomized rats. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Validation in mesenchymal progenitor cells of a mutation-independent ex vivo approach to gene therapy for osteogenesis imperfecta. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Treatment of osteoarthritis using a helper-dependent adenoviral vector retargeted to chondrocytes. Demineralized bone matrix combined bone marrow mesenchymal stem cells, bone morphogenetic protein-2 and transforming growth factor-beta3 gene promoted pig cartilage defect repair. Acceleration of articular cartilage repair by combined gene transfer of human insulin-like growth factor I and fibroblast growth factor-2 in vivo. Nanoparticle delivery of the bone morphogenetic protein 4 gene to adipose-derived stem cells promotes articular cartilage repair in vitro and in vivo. Direct bone morphogenetic protein 2 and Indian hedgehog gene transfer for articular cartilage repair using bone marrow coagulates. Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of Als. Disease-regulated local Il-10 gene therapy diminishes synovitis and cartilage proteoglycan depletion in experimental arthritis. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Il-37 alleviates rheumatoid arthritis by suppressing Il-17 and Il-17-triggering cytokine production and limiting Th17 cell proliferation. Adeno-associated virus-mediated osteoprotegerin gene transfer protects against joint destruction in a collagen-induced arthritis rat model. Direct lentiviral-cyclooxygenase 2 application to the tendon-bone interface promotes osteointegration and enhances return of the pull-out tensile strength of the tendon graft in a rat model of biceps tenodesis. Bone marrow-derived mesenchymal stem cells transduced with scleraxis improve rotator cuff healing in a rat model. Co-transfection of adeno-associated virus-mediated human vascular endothelial growth factor165 and transforming growth factor-1 into annulus fibrosus cells of rabbit degenerative intervertebral discs. The disease affects up to 40% postmenopausal women and 15% elderly men of Caucasian background. Taken together, fragility fracture is a common and serious bone disorder that is expected to increase in magnitude over the next few decades as populations are rapidly aging. Osteoporosis offers an interesting case for the application of genetics in risk prediction, because the susceptibility to the disease is determined by genetic Genetics of Bone Biology and Skeletal Disease. Moreover, osteoporosis is a condition characterized by multiple phenotypes, including worsened bone strength and architecture, and ultimately fragility fracture. Currently, there are multiple treatments and combination of treatments available for reducing bone loss and reducing fracture risk. The efficacy and clinical outcome of current therapies are highly variable among patients. Pharmacogenetics and pharmacogenomics offer the possibility to individualize fracture prognosis and therapy. Pharmacogenetics refers to the science of how genetic factors affect the interindividual variation in drug efficacy and safety. In reality, most pharmacogenetic studies focus on single genes and their associations with interindividual differences in drug behaviors, while pharmacogenomics is concerned with the genomic interactions among genes in the overall variation in drug metabolism and response. Both pharmacogenetics and pharmacogenomics have important applications in studies of the pathogenesis and treatment of osteoporosis. Fracture is a direct consequence of bone fragility and is therefore a key component of an osteoporosis phenotype. However, fracture is a dichotomous event, resulted from cumulative deterioration in multiple tissues, which are in turn linked to genetic and nongenetic factors. Moreover, fracture is age-dependent such that the risk of fracture increases exponentially with advancing age. Theoretically, if the life expectancy of a population were infinite, then the lifetime risk of fracture would be 100%. Therefore, a genetic analysis of fracture as a single phenotype will not adequately capture the dynamics of osteoporosis. Fracture itself is associated with multiple risk factors, some of which may be causal factors. Pooling the results from all studies (women and men) and for all fracture sites, the risk of subsequent fracture among those with a prior fracture at any site is 2. Biochemical markers of bone remodeling can also be considered phenotypes of osteoporosis. Bone mass is the net result of two counteracting processes of bone resorption and bone formation, often referred to as bone remodeling. Bone remodeling is a normal, natural process that maintains skeletal strength, enables repair of bone damage, and is essential for calcium homeostasis. Osteoclasts produce bone degradation products that are also released into the circulation; most of these are cleared via the kidney. These include both enzymes and nonenzymatic peptides derived from cellular and noncellular compartments of bone. It has been proposed to estimate bone formation and bone resorption by serum or urinary biochemical markers. Markers of bone formation and resorption have been shown to be related to bone loss, with higher rates of bone resorption being associated with more rapid bone loss and importantly, with fracture risk. The liability to fracture is therefore a complex phenotype, in the sense that it is a constellation of bone strength and nonskeletal factors, and each of these factors may be determined by specific genes or sets of genes. A key measure of genetic influence on a trait is the index of heritability, which is defined as the extent to 1. In a Finnish twin study, approximately 35% of the variance in the liability to fracture (in both males and females) was attributable to genetic factors. The risk of hip or other fractures was threefold higher with a paternal history of wrist fracture. As for many other multifactorial diseases, osteoporosis is also determined by environmental factors, and possibly by the interaction between environmental and genetic factors. This straightforward design has been used extensively in the field of osteoporosis, but it suffers from a number of shortcomings. The selection of appropriate controls can be a challenge, particularly for fractures that occur mainly in later life. Any statistically significant association between a specific gene variant and fracture may not necessarily indicate a causative relationship, because such an association can have arisen from population stratification and, even when a gene is associated with the fracture outcome, it may not be the gene studied but due to linkage disequilibrium with a causative gene that can be considerably distant along the chromosome. However, the decade in which candidate gene association studies blossomed was also accompanied by frustration with conflicting findings and a lack of independent replication, mainly due to , among other factors, lack of statistical power52 and/or to false positives. Two analytic strategies can be used in genome-wide study: linkage analysis and association analysis. Genome-wide studies, using either linkage or association analysis, are essentially a hypothesis-free approach, because they make no assumptions about the location and functional significance of associated loci or their products, only that there is some locus associated with a phenotype. As such, genome-wide studies can overcome weaknesses of the candidate gene design86,87 by providing a holistic picture of genes that are likely to contribute to the susceptibility of disease. However, genome-wide studies have the major challenge of multiplicity of hypothesis tests. Gene-search studies have been based on the two major approaches, initially candidate gene and more recently genome-wide studies. A common metric of linkage is the log-of-the-odds (lOd) score, which measures the likelihood of linkage compared with no linkage. The discovery of the lrP5 gene has opened up a new chapter of research in the genetics of osteoporosis. The basic idea is to test for differences in allelic frequency of anonymous genetic variants between cases and controls, unadjusted for any current understanding of disease etiology. That is, identified variants may be associated with other variants of potential interest more frequently than expected by chance. The SnP variants may also lie many hundreds of kilobases upstream or downstream from a known putative gene.

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In Wilson disease anxiety purchase phenergan 25 mg without a prescription, abnormal copper metabolism results in accumulation of the metal in the liver anxiety symptoms 24 7 buy phenergan 25 mg free shipping, producing small necrotic lesions leading to cirrhotic nodules and progressive liver damage anxiety symptoms 37 order 25mg phenergan amex, and damage to various areas of the brain anxiety emoji cheap phenergan 25mg without a prescription, especially the lenticular nucleus anxiety symptoms mayo 25 mg phenergan with mastercard. Hepatic dysfunction usually predominates in childhoodonset disease anxiety symptoms mind racing phenergan 25mg low price, whereas adults typically present with neurologic manifestations. Degeneration of the putamen, often forming small the Basal Nuclei 393 good, with diminution of neurologic signs within 5 to 6 months from the onset of therapy. Note the bilateral cavitations in the lenticular nuclei (arrows), hence the name hepatolenticular degeneration. Patients with Wilson disease are all somewhat different; this patient also has noticeable signal changes bilaterally in the thalami. Other patients may show similar changes in the dentate nucleus, pons, or midbrain. This is a childhood autoimmune disease that typically affects children between the ages of 5 and 15 years, and girls are affected more than boys by a ratio of about 2:1. It is a major manifestation of rheumatic fever, which is caused by infection with group A -hemolytic streptococci. The chorea is self-limited and is rarely fatal; fatalities are usually attributed to cardiac consequences of rheumatic fever. The chorea may not appear until 6 months or longer after infection and typically lasts 3 to 6 weeks. Patients present with rapid, irregular, aimless movements of the limbs, face, and trunk. These movements are more flowing and "restless" than those in Huntington disease patients. In addition, patients with Sydenham chorea may have some muscle weakness and hypotonia. Other signs and symptoms may include irritability, emotional lability, obsessive-compulsive behaviors, attention deficit, and anxiety. Fortunately, this is a benign disease, and most patients experience complete recovery from the symptoms. However, about one third of patients may have recurrences of signs and symptoms after several months or even years. The involuntary movements and neuropsychiatric features of Syndenham chorea are thought to result from antibodies produced against the streptococci, which then react with epitopes in the basal nuclei due to molecular mimicry. This concept has led to the use of immunomodulatory therapies to treat Sydenham chorea and related conditions. However, other regions of the brain, including the thalamus, the head of the caudate, and the frontal and cerebellar cortices, may also show similar changes. This degeneration is due to a loss of neurons, axonal degeneration, and increasing numbers of protoplasmic astrocytes. As in other basal nuclear disorders, many patients with Wilson disease will develop psychiatric symptoms, such as changes in personality, argumentative behavior, or emotional lability. However, the motor disturbances are often the most prominent signs and include dystonia, tremor, chorea, dysarthria, and ataxia. The most characteristic form of movement disorder in this disease is a wing-beating tremor, most prominent with the shoulders abducted, the elbows flexed, and the palms facing the floor. Treatment is essential, and the goal is to decrease the amount of copper within the body, thus limiting its toxic effects. Patients should reduce dietary copper intake, and chelating agents such as triethylenetetramine dihydrochloride and penicillamine may be appropriate. Oral zinc also may be helpful by inducing copperbinding metallothionein in enterocytes. Prognosis for patients who have completed the first few years of treatment is very Tardive dyskinesia is a basal nuclear disorder that is iatrogenic in nature, that is, caused by medical intervention for another disease. This condition is caused by chronic treatment with neuroleptic medications, such as the phenothiazines. The condition manifests as uncontrolled involuntary movements, particularly of the face, mouth, and tongue (orobuccolingual dyskinesia). The action of these neuroleptic drugs is to block dopaminergic transmission throughout the brain. The primary target cells are those in the ventral tegmental area that belong to the mesolimbic dopaminergic pathway. Prolonged treatment with neuroleptic drugs may lead to blockage of the D2 dopamine receptors in the striatum, which causes an imbalance in the nigrostriatal influence on the basal nuclear motor loop and ultimately results in movement disorders. Treatment of tardive dyskinesia is complicated by the fact that withdrawal of the causative medication may result in exacerbation of the involuntary movements, as well as worsening of the underlying psychotic state. Medications that may cause tardive dyskinesia should be used with full knowledge of their potential complications and only when other treatments or medications may not be appropriate. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. The ventral basal ganglia, a selection mechanism at the crossroads of space, strategy, and reward. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. The place of the subthalamic nucleus and external pallidum in basal ganglia circuitry. Mihailoff Overview-394 Basic Structural Features-394 Cerebellar Peduncles-394 Cerebellar Lobes, Lobules, and Zones-394 Cerebellar Nuclei-396 Blood Supply to Cerebellar Structures-397 Cerebellar Cortex-397 Purkinje Cell Layer-397 Granule Cell Layer-399 Molecular Layer-402 Cerebellar Afferent Fibers-402 Topographic Localization-403 Synaptic Interactions in the Cerebellar Cortex-403 Functional Cerebellar Modules-405 Vestibulocerebellar Module-405 Vestibulocerebellar Dysfunction-406 Vestibular Connections of the Vermis-406 Spinocerebellar Module-406 Pontocerebellar Module-408 Pontocerebellar Dysfunction-410 Cerebellar Influence on Visceromotor Functions-411 Cerebellum and Motor Learning-412 the cerebellum receives input from many areas of the neuraxis and influences motor performance through connections with the dorsal thalamus and, ultimately, the motor cortices. Lesions of these pathways result in characteristic motor dysfunctions, which may involve either proximal (axial) or distal musculature. These deficits are actually the result of altered activity in the motor cortex and its descending brainstem and spinal projections, which influence lower motor neurons of the spinal cord. First, it receives extensive sensory input, but it is not involved in sensory discrimination or interpretation. Second, although it profoundly influences motor function, lesions of relatively large portions of the cerebellar cortex do not result in lasting motor deficits unless the area of damage also includes portions of the cerebellar nuclei. The patient may have uncoordinated movements, but when tested for strength, the patient is not weak. Large lesions of the cerebellum that involve the cortex plus nuclei may result in significant motor deficits (seen as asynergistic movements) but not in paralysis. Third, lesions of the cerebellum may result in deficits in motor learning and higher mental function. The restiform body is the large ridge on the dorsolateral aspect of the medulla rostral to the level of the obex. This bundle is composed primarily of fibers that form reciprocal connections between the cerebellum and vestibular structures (Table 27. These exiting roots represent the boundary between the basilar pons and the middle cerebellar peduncle. This large peduncle mainly conveys pontocerebellar fibers arise from the pontine nuclei of the basilar pons and enter the cerebellum. Within the midbrain, these fibers cross the midline as the decussation of the superior cerebellar peduncle at the level of the inferior colliculus. This bundle contains predominantly cerebellar efferent fibers that originate from neurons of the cerebellar nuclei and distribute to the diencephalon and brainstem. The cerebellum is further divided into anterior, posterior, and flocculonodular lobes by the primary and posterolateral fissures, respectively. The cerebellum is located superior to the brainstem, inferior to the tentorium cerebelli, and internal to the occipital bone. The cerebellum has a superior surface apposed to the inferior surface of the tentorium and a convex inferior surface that abuts the inner surface of the occipital bone. The inferior peduncle is composed of juxtarestiform (dark green) and restiform (red) bodies. Superior view (C) showing the positions and relationships of the three cerebellar peduncles in a brain specimen. Superimposed on the lobes and lobules of the cerebellum are rostrocaudally oriented cortical zones that are defined on the basis of their connections. On the basis of their afferent and efferent connections, these three larger cortical zones can be subdivided further into nine smaller zones. In general, these zone patterns are the basis for the modules discussed later in this chapter. The clinical deficits that result from a cerebellar lesion depend mainly on which of the three principal zones is involved; consequently, the three-zone terminology is used in this chapter. The lateral (hemisphere) zone occupies by far the largest part of the cerebellar cortex. The fastigial (medial cerebellar) nucleus lies immediately adjacent to the midline and is functionally related to the overlying medial zone of the cerebellar cortex. Lateral to the fastigial nucleus are the two interposed nuclei: the globose (posterior interposed) nucleus and the emboliform (anterior interposed) nucleus. These nuclei are functionally related to the overlying intermediate zone of the cortex. Lateral to the emboliform nucleus is the dentate (lateral cerebellar) nucleus, which appears as a large, undulating sheet of cells shaped like a partially crumpled paper bag. The lobules of the hemisphere are designated by the prefix H, to show which lobule of the hemisphere is continuous with its corresponding (designated by the Roman numeral) vermal lobule. This nucleus is functionally related to the overlying lateral zone of the cortex; its large size correlates with the large size of this cortical zone. Most of the signals that leave the cerebellum do so via axons that arise in the cerebellar nuclei; the remainder travel on fibers that originate in the cerebellar cortex. Collectively, axons that arise in the cerebellar nuclei constitute cerebellar efferent projections. These axons originate from cells in the cerebellar nuclei and generally use one of the excitatory neurotransmitters, glutamate or aspartate, and thus function to activate their targets. The fastigial nuclei generally project bilaterally to the brainstem through the juxtarestiform bodies. Some neurons in each cerebellar nucleus send axons or axon collaterals into the overlying cortical zone, where they terminate in the granular layer as mossy fibers. These axons are called nucleocortical fibers, and they exert an excitatory influence on the cerebellar cortex. Each Purkinje cell gives rise to an elaborate dendritic tree that radiates into the molecular layer. The "trunk" of the tree is a single primary dendrite, which gives rise to several secondary dendrites, which in turn branch into many tertiary dendrites. Smooth branchlets emerge from secondary and tertiary dendrites, whereas spiny branchlets (covered by minute structures called gemmules) arise mainly from tertiary dendrites. In rostral views (A and E, J), the folia of the anterior lobe can characteristically be followed across the midline. The tonsil and its close relationship with the medulla are seen in inferior views (B and G, H); the peduncles and the lobes are clearly evident in anterior (ventral) views (C and H, I). Purkinje cell axons arise from the basal aspect of its pear-shaped cell body and may give rise to recurrent collaterals. These axons traverse the granular layer and the subcortical white matter to eventually terminate in either the cerebellar or the vestibular nuclei. Purkinje cells projecting into the cerebellar nuclei (as cerebellar corticonuclear fibers) arise from all areas of the cortex, whereas those projecting into the vestibular nuclei (as cerebellar corticovestibular fibers) originate primarily from parts of the vermis and the flocculonodular lobe. The general areas of cortex and nuclei served by the cerebellar arteries are also indicated on the left. Roman numerals indicate lobules of the vermis; numerals preceded by H indicate the corresponding lobules of the hemisphere. Granule Cell Layer There are three main types of neuron cell bodies within the granule layer. These are granular cells, which are extraordinarily numerous and found in all areas of the cerebellar cortex; Golgi cells, which are larger and also widely distributed; and unipolar brush cells, which are small neurons that have a restricted geographic distribution within the cortex. Their axons ascend into the molecular layer, where they bifurcate to form parallel fibers. As indicated by their name, parallel fibers run parallel to the long axis of the folium. They also synapse with the cells intrinsic to the molecular layer, such as basket and stellate cells. Granule cells use glutamate (or perhaps aspartate) as their neurotransmitter and thus have an excitatory effect on their target cells. In fact, the granule cells are the primary excitatory neurons of the cerebellar cortex. The unipolar brush cell is also excitatory but is found in strikingly fewer numbers and is restricted in its distribution within the cortex. All of the other neurons of the cerebellar cortex, as we shall see, are inhibitory. Dendrites of Golgi cells branch in the granular layer but extend primarily into the molecular layer without regard to plane of orientation. The third neuronal type found within the granule layer is the unipolar brush cell. This dendritic process ends in a brush-like configuration made up of a cluster of dendrioles.

A mouse model for spondyloepiphyseal dysplasia congenital with secondary osteoarthritis due to a Col2a1 mutation anxiety symptoms heart 25mg phenergan visa. Endoplasmic reticulum stress-unfolding protein response-apoptosis cascade causes chondrodysplasia in a col2a1p anxiety symptoms related to menopause order phenergan 25 mg free shipping. Young mice have a variable phenotype of a chondrodysplasia and older mice have osteoarthritic changes in joints anxiety symptoms for no reason purchase phenergan 25 mg amex. Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function anxiety therapist generic phenergan 25mg without a prescription. Osteoarthritis-like changes and decreased mechanical function of articular cartilage in the joints of mice with the chondrodysplasia gene (cho) anxiety symptoms nail biting buy phenergan 25mg line. Hemizygous males: small size; domed skull; short limbs; cleft palate; embryonic death y 1 anxiety disorder test discount phenergan line. Homozygotes: perinatal death; scoliosis; delayed ossification Homozygotes: perinatal death due to respiratory distress; growth retardation; shortened limb long bones; abnormal sternum and rib cage; shortened maxillary and mandibular bones; reduced chondrocyte numbers in growth plates; abnormal temporomandibular joints Homozygotes: slightly shortened long bones; severely shortened digits; altered digit patterning Heterozygotes: hypoplastic clavicles and nasal bones; reduced ossification Homozygotes: immediate perinatal death; dwarfism; short limbs; very little or no ossification. Homozygotes: normal intramembraneous ossification; absence of endochondral ossification Homozygotes: perinatal death within 24 h; diminished bone formation; absent clavicle and occipital bone; decreased trabecular number and increased trabecular separation. Immediate postnatal death due to respiratory failure; absent vertebrae, pelvic, scapula and metacarpal/metatarsal bones; short ribs and limb bones; craniofacial bones poorly developed or absent Perinatal death; domed skull, short snout, small limbs; reduced ossification; disorganized growth plates. Malignant autosomal recessive osteopetrosis caused by spontaneous mutation of murine Rank. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of bone morphogenic protein signaling and severe skeletal defects. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice. Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia. Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. Tissue-nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the Alpl-/- mouse model of infantile hypophosphatasia. Bone mineralization-dependent craniosynostosis and craniofacial shape abnormalities in the mouse model of infantile hypophosphatasia. Novel mouse model of autosomal semidominant adult hypophosphatasia has a splice site mutation in the tissue nonspecific alkaline phosphatase gene Akp2. Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling. The partial purification of growth-inhibiting factor of the brachypodism-H mouse embryos. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Runx2-I isoform contributes to fetal bone formation even in the absence of specific N-terminal amino acids. Chondrocyte-specific regulatory activity of Runx2 is essential for survival and skeletal development. Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Modification of guanine with the ethyl group to produce o6-ethylGuanine (o-eG), causes mispairing during DnA replication, for example, at spermatogenesis, and during subsequent replication a mutation is introduced. Males with phenotypic abnormalities of interest are then mated with wild-type females to facilitate inheritance testing and genetic mapping in affected offspring (G2) to identify the mutation causing the phenotypic abnormality. DnA and sperm from all the G1 males are also archived to facilitate genotype-driven screens. Filled/striped boxes denote coding sequences and open boxes denote noncoding sequences. Archived DnA samples from the mutagenized male mice are used to search for mutations in the gene of interest, and once mutations are identified in the mouse DnA, then the corresponding sperm sample for the male mouse harboring the mutation is used to establish progeny carrying the mutation by in vitro fertilization. The vector is either electroporated or retrovirally infected into embryonic stem (eS) cells, after which it randomly inserts into the genome. A recent refinement of the gene-trap strategy is targeted trapping, in which the vector also contains regions homologous to the targeted gene, thereby facilitating the deletion of a specific gene. The targeting vector is transferred to the eS cells, and those in which homologous recombination or integration has been successful are selected. These are injected into the inner cell mass of a blastocyst from a different mouse strain [e. The resulting chimeric offspring (usually males are selected) are bred with wild type, for example, c57Bl/6 mice (usually females are selected) to achieve germline transmission. Integration of the neoR gene (and therefore the targeting construct) into the eS cell genome allows these eS cells to survive normally toxic amounts of antibiotic treatment, thereby allowing selection of eS cells that have been successfully targeted by homologous recombination. To further facilitate the selection of eS cells that have undergone successful targeting by homologous recombination, a negative selection cassette, such as the Herpes Simplex virus thymidine kinase (Tk) gene, may also be used. In the presence of a thymidine analog in the growth medium, eS cells containing the Tk cassette. These "conventional" knock-out models have proved to be very useful in studies of human diseases, although their use may be limited if the disruption of the gene in a critical organ results in early death, for example, at any embryonic stage. The inducible models utilize a fusion protein, such as a modified ligand-binding domain of the estrogen receptor fused to the cre (creeR) or FlP gene, which on administration of an estrogen receptor antagonist (tamoxifen), translocates to the nucleus to excise the floxed allele(s), thereby allowing the gene to be permanently knocked out at the desired time, which may be either during embryonic or neonatal development, or in adult life. However, knock-out models are not always the most appropriate, particularly when the human disease being studied is not due to a loss-offunction or null allele for the gene. Thus, to generate appropriate murine models for these diseases, the specific mutation needs to be introduced into the mouse genome, and this may be achieved by targeted knock-in or transgenic approaches (Tables 7. In addition, the positive selection cassette is normally placed in an intron and floxed so that it can be excised and cause minimal effects on gene expression. The general approach relies on the ability to target nucleases to specific DnA sequences. Furthermore, a single cas protein introduces double strand breaks, and hence only one cas protein is needed for each target site. As reviewed later, these different strategies for generating mouse models of human diseases have greatly facilitated studies of inherited bone and mineral disorders that have investigated mechanisms and treatments, which would not be easily feasible in patients. These abnormalities of calcium homeostasis may be associated with hypocalcemia (Tables 7. Targeting vectors (dotted lines/striped boxes) typically consist of two "arms" of sequence homologous to the target gene flanking a positive selection cassette, such as the neomycin phosphotranserase (neoR) gene, and with a negative selection cassette, such as the thymidine kinase (Tk) gene at one end of the construct. The neoR cassette is usually flanked by two loxP sites (open triangles) so that it may be removed by expression of cre recombinase after homologous recombination (dashed lines) with the host (wild-type) genome (solid lines). Thick lines denote sequences derived from genomic DnA, with filled/striped boxes representing coding exons and open boxes representing noncoding exons; thin lines denote sequences derived from vectors. In a typical conventional knock-out targeting vector, the neoR cassette replaces one or more exons, and is then excised by cre recombinase after homologous recombination. Part of the coding region of the gene is also flanked by loxP sites (open triangles). Thus, when homozygote mutant mice are crossed with mice expressing cre in a tissue-specific manner, or mice expressing an inducible cre, the gene is knocked-out within the tissue or upon administration of the inducer. A specific mutation is introduced into the targeting vector (asterisk), usually by site-directed mutagenesis. The neoR cassette is placed in an intron close to the mutation and excised after homologous recombination, either by introduction of cre recombinase into the eS cells, or by breeding mutant mice with mice with ubiquitous cre expression. The guide RnA binds to the sequence of interest and recruits the cas protein, which introduces a double strand break into the DnA. If a repair template is included, homologous repair can be achieved, which may be used to introduce any mutation of interest and generate a knock-in model. It arises from a congenital failure in the development of the derivatives of the third and fourth pharyngeal pouches, with resulting absence or hypoplasia of the parathyroids and thymus. Thus, heterozygous (Tbx1+/-) mice have cardiac outflow tract abnormalities, which are defects of the fourth branchial pouch. Several tissue-specific murine knock-out models of Tbx1 have also been generated (Table 7. Thus, mice with osteoprogenitor-specific knock out of Tbx1 exhibited reduced ossification of the hyoid bone, significantly smaller parietal bones, and hypoplastic clavicles. Pth heterozygous (Pth+/-) mice were viable with no apparent phenotypic abnormalities. Pth-/- mice also had abnormal skull formation with enhanced mineralization, shortening of the long bones and other skeletal abnormalities. However, Gcm2-/- mice have no parathyroid glands, resulting in hypocalcemia and hyperphosphatemia, consistent with hypoparathyroidism. Gcm2-/- mice also have a mild bone phenotype, consisting of a low number of osteoclasts and osteoblasts, and increased bone volume. Heterozygous knock-out mice lacking exon 1 or exon 2 of Gnas1 have decreased postnatal survival. These ossifications consisted of mineralized bone, which expressed osteoblast markers, such as osteopontin and osteonectin. Thus, Casr-/- Pth-/- mice did not have increased neonatal lethality or skeletal abnormalities. Casr-/- Cyp27b1-/- mice had improved survival rates and body size compared to Casr-/- mice, and normocalcemia. The Casr was electively knocked out in growth plates before birth, and this also resulted in bone defects, such as short bones, as well as a decrease in mature and terminally differentiated chondrocytes. The hypocalcemia is usually mild and asymptomatic, but may sometimes be associated with tetany and seizures. In addition, mutant mice may also have widespread ectopic calcification and suffer from sudden death. These murine models have also helped to increase our understanding of the relationships between different signaling components involved in skeletal biology, and calcium and phosphate homeostasis. Mouse models as preclinical models also provide opportunities for assessing future novel therapies for bone and skeletal disorders. Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. Pex/PeX tissue distribution and evidence for a deletion in the 3 region of the Pex gene in Xlinked hypophosphatemic mice. Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia. Partial deletion of both the spermine synthase gene and the Pex gene in the X-linked hypophosphatemic, gyro (Gy) mouse. Activating calciumsensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Gene targeting using a promoterless gene trap vector ("targeted trapping") is an efficient method to mutate a large fraction of genes. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Deficiency of the G-protein alpha-subunit G(s)alpha in osteoblasts leads to differential effects on trabecular and cortical bone. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Rickets in cation-sensing receptor-deficient mice: an unexpected skeletal phenotype. Spectrum of enu-induced mutations in phenotype-driven and gene-driven screens in the mouse. A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11.