Mark Corson

Internal resorption should be considered to be a form of irreversible pulpitis and treated without delay buy discount rosuvastatin 20mg on-line. Following standard access cavity preparation order rosuvastatin 10mg visa, the pulp chamber and coronal portion of the canal is usually found to contain necrotic debris rosuvastatin 5mg with visa. However, deeper penetration of the canal often provokes torrential haemorrhage as the vascular, resorptive tissue is entered. Root canal preparation is undertaken in the usual manner, and following apical enlargement, haemorrhage from the canal is greatly reduced as the blood supply to the resorptive tissue is severed. Instrumentation of the expanded, resorbed area is difficult, and can be greatly enhanced by the use of sonic or ultrasonic devices which are able to throw irrigant into uninstrumented areas. The antimicrobial and tissue solvent actions of sodium hypochlorite make it the irrigant of choice in such cases. As in the case of external inflammatory resorption, it is usual to dress the canal with non-setting calcium hydroxide following debridement. This may be highly advantageous in the internal resorption case where the antimicrobial and mild tissue solvent actions of calcium hydroxide may be exploited further to clean the resorbed area. Obturation may then be undertaken with gutta percha and sealer, usually employing a thermoplastic technique to allow satisfactory condensation and adaptation in the resorbed area (Fig. Where internal reinforcement is indicated, dual curing composite resin and fibre posts may offer some advantages over full canal filling with gutta percha and sealer. If more than 20% of the periodontal ligament is damaged or lost and the tooth is subsequently reimplanted, bone cells are able to grow into contact with the root surface more quickly than the remaining periodontal fibroblasts are able to recolonize the root surface and intervene between tooth and bone. The consequence is that the root now becomes involved in the normal remodelling process of the bone in which it is implanted, and is gradually replaced by bone over the course of the following years. In young children where the rate of bone remodelling is high, the root may be entirely lost within 3-4 years. The absence of a ligamentous joint between the tooth and its supporting bone (ankylosis) means that even when root resorption is advanced, the tooth will appear rock solid. Radiographically, the root will appear ragged in outline, with no obvious periodontal ligament space separating it from the surrounding bone (Fig. There is no effective treatment for ankylosis but the rate of progression is relatively slow and the tooth can be maintained for 10 years or more. There is no effective treatment for established replacement resorption and parents and carers should be advised of the inevitable course of events. From an endodontic point of view, it is important to reiterate that if pulp extirpation is undertaken within 2 weeks of reimplantation then the initial root canal dressing should be an antibiotic/steroid (Ledermix, Lederle) preparation which should be replaced subsequently with non-setting calcium hydroxide, no sooner than 2 weeks after tooth reimplantation. If endodontic treatment was not undertaken soon after reimplantation and the tooth subsequently loses vitality, conventional root canal therapy may be undertaken in order to address any painful periapical pathosis and to avoid the additional insult of inflammatory resorption which would lead to more rapid loss of root substance. A resorbable root filling material such as root canal sealer alone or reinforced zinc oxide eugenol cement may be preferred to gutta percha in some cases. Where resorption is progressive then consideration should be given to autotransplantation of either an upper second premolar or lower first or second premolar if any of these teeth were to be removed as part of an orthodontic treatment plan. If autotransplantation is completed while the root of the premolar is about two- thirds formed then there is a good chance of revascularisation and further root growth (Fig. If the autotransplanted tooth has a mature apex then revasculariztaion is unlikely and the tooth should be exptirpated at splint removal and the canal dressed with antibiotic/steroid (Ledermix/Lederle) initially, then non-setting calcium hydroxide. The tooth can be obturated with gutta percha when there is no evidence of progressive resorption. Key Points Pathological root resorption • inflammatory: external (including cervical)and internal; • inflammatory may arrest if cause is removed; • replacement resorption is not amenable to treatment; • maintain a resorbing tooth for as long as possible. Usually presents as an asymmetrical radiolucency on the lateral surface of the root. If the lesion overlies the root canal, its lateral walls are usually still visible. Maxillary central incisor demonstrating internal resorptive defects at two levels. The canal was cleaned, shaped, and obturated with thermoplasticized gutta percha and sealer. There is a reduced response to vitality testing and the crown appears slightly yellow/opaque. The exact initiating factor which produces this response from the odontoblasts is unknown. It is more common in immature teeth and in luxation injuries rather than in concussion and subluxation injuries. Although radiographs may suggest complete calcification there is usually a minute strand of pulpal tissue remaining. The segment of alveolus with teeth requires only 3-4 weeks of rigid splintage (composite-wire type) with two abutment teeth either side of the fracture, together with antibiotics, chlorhexidine, soft diet, and tetanus prophylaxis check (Fig. Each week 2-3 children in Britain and 80 children in the United States will die as a result of abuse or neglect. At least one child per 1000 in Britain suffers severe physical abuse; for example, fractures, brain haemorrhage, severe internal injuries or mutilation, and in the United States more than 95% of serious intracranial injuries during the first year of life are the result of abuse. Although some reports will prove to be unfounded the common experience is that proved cases of child abuse are four to five times as common as they were a decade ago. Physical abuse is not a full diagnosis, it is merely a symptom of disordered parenting.

Drugs will be targeted better to diseases in particular patients based on genotype information discount rosuvastatin 5mg fast delivery. The epigenome is involved in regulation of gene expression discount 20 mg rosuvastatin amex, development cheap 20 mg rosuvastatin fast delivery, and tissue differentia- tion. Unlike the underlying the genome which is largely static within an individual, the epigenome can be altered by environmental conditions. Whereas epigenetics often refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. Neurological disorder are not only associated with genomic mutations and tran- scriptomic dysregulations, but with changes in the epigenome. Universal Free E-Book Store Neuroproteomics 413 Targeting the complete mitochondrial exome provides a greater potential to identify rare variants that disrupt normal mitochondrial function, enabling an exact diagnosis in a large proportion of patients that remain undiagnosed by other meth- ods. Over 95 % of the target bases can be sequenced to an average coverage of 400×, providing highly accurate and sensitive results. Neuroproteomics The role of proteomics in personalized medicine has been described in Chap. Neuroproteomics is the term used for application of proteomics to the study of the nervous system and its disorders with the aim of developing diagnostics and thera- peutics (Jain 2002). Proteomics tools offer new ways to analyze networks of pro- teins that control important neurobiological phenomena. Neuroproteomics, combined with bioinformatics, can be used to study the organization of functional protein networks and molecular structures that underlie physiological, anatomical, and behavioral processes (Bayés and Grant 2009 ). Applications of Neuroproteomics for Study of the Nervous System Proteomics technologies are used for the study of neurotransmitters and neuronal receptors. A brief description of these is as follows (Jain 2013): Neurotransmitters Capillary electrophoresis has been combined with highly sen- sitive micro-electrospray-tandem mass spectrometry to simultaneously detect classi- cal small molecule neurotransmitters as well as neuropeptides from discrete regions of the brain. Endogenous glutamate, gamma-aminobutyric acid, acetylcholine, and dopamine as well as the neuropeptides methionine-enkephalin and substance P 1–7 could be detected in the striatum using only a minute amount of brain tissue. Neuroprotection Use of neuroproteomics, systems biology, and bioinformatics aim to study and establish a global assessment of the entire neuronal proteome (Raad et al. Neuroproteomics aids in the understanding of molecular mecha- nisms of neurogenesis. Potential neuroprotective pharmacological strategies can be targeted at Rho and Rho kinases, which constitute key integral points in the pathway that is known to be disrupted in multiple neuropathologies, such as spinal cord injury and traumatic brain injury (Jain 2011 ). Universal Free E-Book Store 414 12 Personalized Management of Neurological Disorders Regeneration and Degeneration of the Nervous System Neuroproteomic tech- nologies have been designed to uncover the mechanisms and molecules involved in neuronal regeneration and degeneration (Sun and Cavalli 2010). Most proteins mediating regeneration are found to be either malfunctioning or reduced in degeneration. These studies are further facilitated by the availability of 2D maps of brain-specific proteins. Role of neuroproteomics in the management of individual disorders will be described in sections dealing with these disorders. Some disease-specific proteins identified in the cerebrospinal fluid of patients with neurologic disorders are shown in Table 12. Concentrations of the S-100 protein, an acidic calcium-binding protein found in the gray matter of the brain, are elevated in serum after brain damage. However, this test does not replace brain biopsy for definitive diagnosis of Creutzfeldt-Jakob disease. Undetectable S-100 in the blood of patients with head injury can rule out brain damage, and S-100 levels correlate with the extent of brain damage in severe head injury. Peak levels of serum S-100 correlate with neu- rologic deficit resulting from either stroke or traumatic brain injury, and the patterns can be used to differentiate between the two conditions. Elevated serum levels of S-100 in patients with liver cirrhosis indicate early and subclinical portal-systemic encephalopathy. It seems to be a promising biochemical sur- rogate marker for mild cognitive impairments due to portal-systemic encephalopathy. Neuron-Specific Enolase This is a glycolytic enzyme found in the neurons and neuroendocrine cells. Increased levels of neuron-specific enolase have been measured as a result of ischemic stroke in cerebral spinal fluid as well as in blood. Universal Free E-Book Store 416 12 Personalized Management of Neurological Disorders Table 12. Peak levels of both neuron-specific enolase and S-100 are statistically significant and correlate with clinical measures of stroke size and outcome. Myelin Basic Protein This is localized in the myelin sheath and constitutes approximately one third of the total protein of myelin from the human brain. Various studies have indicated that myelin basic protein concentrations in plasma and serum can be used as biomarkers for brain damage and severity of stroke. The increase of myelin basic protein in cerebral infraction is most evident several days after the onset, whereas in cerebral hemorrhage, the peak increase occurs almost immedi- ately after the onset. Neurodegenerative dis- eases with underlying protein abnormalities are shown in Table 12. Further understanding of these mechanisms may lead to strategies for prevention of neuro- degenerative diseases and to the development of effective drugs. Identification of neurodegeneration-associated changes in protein expression will facilitate the iden- tification of novel biomarkers for the early detection of neurodegenerative diseases and targets for therapeutic intervention. This will also accelerate development of specific diagnostic and prognostic disease biomarkers. Universal Free E-Book Store Personalized Biological Therapies for Neurological Disorders 417 Neurometabolomics Role of metabolomics in personalized medicine was described in Chap.

Finally generic 10mg rosuvastatin overnight delivery, such a genetic asthma test will allow physicians to tailor therapy for asthmatics; aggressive treatment for individuals at risk for severe disease and mini- mal treatment (avoiding the risk of medication side effects) for those at low risk cheap rosuvastatin 5 mg visa. Approximately 16 % of the population will be homozygous for the genotype responsible for the more limited response to inhaled glucocorticoids order rosuvastatin 20mg on line. For personalization of treatment of asthma to become a reality, the next step should be to conduct clinical trials in which patients are stratified according to their biologic signatures to determine whether knowledge of this information leads to better clinical outcomes (Drazen 2011 ). Genetic Polymorphism and Response to β2-Adrenergic Agonists Inhalation of salbutamol, a β2-adrenergic agonist that has a bronchodilator effect in asthma, aids the flow of air to the lungs. However, the issue of whether regular use of an inhaled β2- adrenergic agonist worsens airflow and clinical outcomes in asthma is controver- sial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at amino acid residue 16 of the β2-adrenergic receptor. A genotype-stratified, randomized, placebo-controlled cross-over trial found that over time the study participants’ responses to daily doses of inhaled albuterol dif- fered depending on which form of a specific gene they had inherited (Israel et al. While a few weeks of regular use of albuterol improved overall asthma con- trol in individuals with one form of the gene, stopping the drug eventually improved asthma control in those with another form of the gene. Genotype at the 16th amino acid residue of the β2-adrenergic receptor affected the long-term response to alb- uterol use. It was recommended that bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype. Lebrikizumab improves lung function in adult asthma patients who are unable to control their disease on inhaled corticosteroids. Increased levels of periostin, a biomarker of asthma, can be measured in the blood. The primary endpoint of the trial showed that at week 12, lebrikizumab-treated patients had a 5. These results support further investigation of lebrikizumab as a personalized medicine for patients who suffer from moderate to severe uncontrolled asthma periostin enables selection of patients who will benefit most from the drug. It is predicted to be the third largest cause of death by 2020 and has already reached worldwide epidemic proportions. The natural history of this disease is generally characterized by contin- ued decline in lung function, which is highly variable. Bronchial biopsies and bronchoalveolar lavage provide valuable informa- tion about inflammatory cells and mediators, but these procedures are invasive, so that repeated measurements are limited. Analysis of exhaled breath is a noninvasive procedure so that repeated measurements are possible, but the variability is high for some assays. There is relatively little information about how any of these biomarkers relate to other clinical outcomes, such as progression of the disease, severity of disease, Universal Free E-Book Store 522 15 Personalized Management of Pulmonary Disorders clinical subtypes or response to therapy. In the future pulmonary biomarkers may be useful in predicting disease progression, indicating disease instability and in predicting response to current therapies and novel therapies, many of which are now in development. Other causes are neuromuscular impairment, pulmonary edema, pneumonia, and vascular diseases such as acute or chronic pulmonary embolism. When a patient is admitted into the hospital with a severe lung failure, it usually takes >3 months to get to 80 % of his or her baseline health. If the patient’s health is poor to start with, the new attack can be devastating or even fatal. There is need for a test that could be performed in any clinical lab and could be used far more widely than the current lung function tests, which are performed in certain centers by specially trained personnel. The subgroup of airway epithelial cells belonging to the diffuse neuroendocrine system, termed pulmonary neuroendocrine cells, may represent a putative regulatory function of CgA as a prohormone. They are considered to control growth and development of the fetal lung and regulation of ventilation and circula- tion, but may also have a role in the pathogenesis of smoking-induced airway disease. The findings indicate that neuroendocrine activation may be important in smoking- related airway inflammation and remodeling, and raise the possibility that CgA could be of predictive value as a biomarker of prognosis in smoking-associated diseases. Correlation of gene expression with lung function measurements identified a set of 86 genes. A total of 16 biomark- ers showed evidence of significant correlation with quantitative traits and differential expression between cases and controls. Reduction of risk factors emphasizes the importance of smoking cessation and control of environmental indoor and outdoor pollutants. Comparisons between gene expression patterns of various diseases have been used to identify disease-specific pathway dysregulation that can be targeted with pathway-directed medications. Diagnosis is by exclusion of other lung diseases and the only definite diagnosis is by lung biopsy but it carries some morbidity and mortality. Biomarkers of Interstitial Lung Disease Pulmonary Surfactant Proteins as Biomarkers for Lung Diseases Pulmonary surfactant, a complex of lipids and proteins, functions to keep alveoli from collapsing at expiration. Pulmonary collectins directly bind with broad specificities to a variety of microor- ganism and possess antimicrobial effects. The collectins enhance phagocytosis of microbes by macrophages through opsonic and/or non-opsonic activities. The pro- teins stimulate cell surface expression of phagocytic receptors including scavenger receptor A and mannose receptor. Developing Personalized Therapies for Interstitial Lung Disease There is a need for therapeutic approaches that target molecular pathways to modu- late aberrant processes and promote tissue homeostasis in the lung. However, the com- plex tasks of making a definite diagnosis of a specific form of interstitial lung dis- ease and formulating a patient-centered, personalized management plan in an attempt to achieve remission or stabilization of the disease process poses a chal- lenge to clinicians (Meyer 2014).

Concurrence of Pendred endothelin-B receptor gene in a family with Waardenburg- syndrome purchase rosuvastatin 10mg amex, autoimmune thyroiditis and simple goiter in one family safe rosuvastatin 10 mg. Am J Med obstruction and deafness: a developmental “neural-crest syndrome” Genet 1983; 14:231–239 buy rosuvastatin 20 mg without prescription. Acta cephalus and trapeze aplasia; implications for the mapping of the Radiol 2001; 42:320–322. A gene locus for branchio-otic type-phenotype correlation in hearing loss with enlargement of syndrome maps to 14q21. Genome-wide search and genetic localization of a sec- J Med Genet 2005; 42:159–165. Due to the lack of vision and hearing, the subject has Deafblindness comprises a number of heterogeneous hearing to rely on sensory influx from smell, taste, and touch. These disorders can be caused by trauma, gives a severe risk of sensory deprivation, which might enhance diseases, and different genetic syndromes. Subjects with congenital deafblind- ing and vision are the primary communication tools for ness need an environment with extremely good professional humans; their action is complementary and they enhance each communication skills. To be fast and reliable, communication between humans and relies heavily on tactile sign language and input via the relies on vision and hearing. When working from the Latin word “communicare,” which means to do things with persons with congenital deafblindness, the goals have so together, it is obvious that a loss of these two senses can be cat- far been to open new channels for communication. Likewise, when vision is If a child with congenital deafblindness does not have severe poor, hearing plays a major role in the localisation of sounds brain damage, early cochlear implantation might result in hear- and detection of danger etc. A person with deafblindness can be pro- sound awareness and basic recognition of sounds. As mentioned before, vision implants have not yet proved to be successful but ongo- vision and hearing interact, thus deafblindness is 1 1 3. A widely used definition is by the Northern European com- Today (2006), at least 20 different genetic syndromes are mittee on disability who in 1980 stated as follows: A person is known to cause congenital deafblindness. In some of these, the deafblind when he/she has a severe degree of combined visual genes have been identified and cloned. Some deafblind people are totally these genetic conditions and difficulties in assessment, congen- deaf and blind, whereas others have residual hearing and resid- ital deafblindness can sometimes be missed and hidden due to ual vision. Another categorisation of deafblindness is to discuss these disorders as either congenital or acquired deafblindness. Acquired deafblindness As in congenital deafblindness, there are many causes of acquired Congenital deafblindness deafblindness. The prevalence of acquired deafblindness is hard Congenital deafblindness is extremely rare: about 1 in 10,000 to estimate, in part depending on the definition. Causes of congenital deafblindness young and middle-aged people are included and most of the syn- include genetic syndromes, premature birth, infections, etc. It should be noted, however, that in 56 Genetics and hearing impairment old people, a severe hearing loss as well as a severe visual loss Table 4. The audiogram might sometimes show a little residual is an autosomal recessive disorder. The profound in different countries but approximately 50% of all people deafness does not allow development of speech. The next to made early in life (before two years of age), the results are describe the disease was Charles Usher in 1914. Another well as benefiting sound localisation later in life when vision historic landmark was the recognition by Julia Bell in 1933 of deteriorates. The first visual symptoms can be observed The disease in the retina is degeneration. The child is insecure in darkness, clumsy, “bones spicules,” which are caused by release of pigment from etc. The fundus changes are seen rather late, thus the first reli- the pigment epithelium, forming black spots in the retina. The clinical classification is at present based on three This is easily assessed in small children by using video-Frenzel Deafblindness 57 during rotation. Thus screening for vestibular deficiency in deaf mild progression can be seen from the fourth decade. The hear- and hearing-impaired children, and a finding of a bilateral ing benefits from bilateral hearing aid amplification as early as vestibular areflexia, will in approximately 30% to 40% of these possible. The gene is linked to chromosome 1q and the mutation 2299delG is the expressed in many organs. The mutations present (2005) more than 80 different mutations have been are found in a gene named Usherin, which codes for a novel reported. Its exact function is and was first described in the French Acadian population of still unclear. Genetic testing and is suggested to play a role in transmission of nerve is available on a clinical basis. The gene is not ■ Usher type Id: This condition is linked to chromosome 10q known (18). A mouse model for Usher type Id, called the Waltzer and has so far been reported in four families. The protein is related to oto- rapid and results in acquired profound deafness at the age of 30 cadherin and the gene is expressed both in the retina and in to 40 years (21).